Tetracyclic compounds and uses thereof

ABSTRACT

The present disclosure relates generally to certain tetracyclic compounds, pharmaceutical compositions comprising said compounds, and methods of making said compounds and pharmaceutical compositions. The compounds of the disclosure are useful in treating or preventing human immunodeficiency virus (HIV) infection.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/980,857 filed on Feb. 24, 2020, U.S. Provisional Application No.63/036,268 filed Jun. 8, 2020, and U.S. Provisional Application No.63/128,670 filed Dec. 21, 2020. The entire contents of theseapplications are incorporated herein by reference in their entirety.

FIELD

This disclosure relates generally to certain tetracyclic compounds,pharmaceutical compositions comprising said compounds, and methods ofmaking and using said compounds and pharmaceutical compositions.

BACKGROUND

Human immunodeficiency virus infection and related diseases are a majorpublic health problem worldwide. Human immunodeficiency virus encodesthree enzymes which are required for viral replication: reversetranscriptase, protease, and integrase. Although drugs targeting reversetranscriptase and protease are in wide use and have shown effectiveness,particularly when employed in combination, toxicity and development ofresistant strains may limit their usefulness (Palella, et al. N. Engl. JMed. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001).Accordingly, there is a need for new agents that inhibit the replicationof HIV.

A goal of antiretroviral therapy is to achieve viral suppression in theHIV infected patient. Current treatment guidelines published by theUnited States Department of Health and Human Services provide thatachievement of viral suppression requires the use of combinationtherapies, i.e., several drugs from at least two or more drug classes(Panel on Antiretroviral Guidelines for Adults and Adolescents.Guidelines for the Use of Antiretroviral Agents in Adults andAdolescents Living with HIV. Department of Health and Human Services.Available athttps://files.aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.Accessed Feb. 20, 2020). In addition, decisions regarding the treatmentof HIV infected patients are complicated when the patient requirestreatment for other medical conditions. Because the standard of carerequires the use of multiple different drugs to suppress HIV, as well asto treat other conditions the patient may be experiencing, the potentialfor drug interaction is a criterion for selection of a drug regimen. Assuch, there is a need for antiretroviral therapies having a decreasedpotential for drug interactions.

In addition, the HIV virus is known to mutate in infected subjects(Tang, et al. Drugs (2012) 72 (9) e1-e25). Because of the proclivity ofthe HIV virus to mutate, there is a need for anti-HIV drugs to beeffective against a range of known HIV variants (Hurt, et al. HIV/AIDSCID (2014) 58, 423-431).

For certain patients, for example, those with difficult or limitedaccess to health care, adherence to daily oral treatment or prophylacticregimens can be challenging. Drugs that offer favorable pharmaceuticalproperties (for example, improved potency, long-acting pharmacokinetics,low solubility, low clearance, and/or other properties) are amenable toless frequent administration and provide for better patient compliance.Such improvements can, in turn, optimize drug exposure and limit theemergence of drug resistance.

SUMMARY

In one aspect, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is a H, C₆₋₁₀aryl or C₆₋₁₀heteroaryl, wherein the C₆₋₁₀aryl        or C₆₋₁₀heteroaryl is optionally substituted with one to four        R^(A1), wherein each R^(A1) is independently halo, C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl,        —O—C₃₋₆cycloalkyl, or C₁₋₄alkyl-O—C₁₋₄alkyl;    -   Y is selected from the group consisting of —C(O)NH—,

-   -   L is —CR^(3a)R^(3b)—, —C(O)—, —SO₂—,        —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, or —N(R^(a))—;    -   W¹ is a bond or —CR^(4a)R^(4b)—;    -   W² is —CR^(5a)R^(5b)—, —CR^(5a)R^(5b)CR^(5c)R^(5d)—,        —CR^(6a)═CR^(6b)—, —N(R⁷)—, —O—, —S(O)_(n)—, —C(O)NR^(e)—,        —CR^(5a)R^(5b)—N(R⁷)—, —CR^(5a)R^(5b)—O—,        —CR^(5a)R^(5b)—S(O)_(n)—, —CR^(5a)R^(5b)—C(O)NR^(e)—,        —CR^(5a)R^(5b)—NR^(e)—C(O)—, —S(O)_(n)N(R^(e))—CR^(5a)R^(5b)—,        or —N(R^(e))—S(O)_(n)—CR^(5a)R^(5b)—;    -   X is a bond or —CR^(8a)R^(8b)—;    -   Z is —CR^(9a)% R^(9b)—, —CR^(9a)R^(9b)CR^(9c)R^(9d)—, or        —CR^(10a)═CR^(10b)—;    -   T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d) and U is        —NR¹¹—, —CR^(12a)R^(12b)—, —S(O)_(n)—, —C(O)—, or —O—; or T and        U together are

-   -   R^(2a), R^(2b), R^(2c), R^(2d), R^(12a), and R^(12b) are        independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),        —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NHR^(a)—,        —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)— —NR^(e)—S(O)_(n)R^(a)—,        —S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or    -   any one of (i) R^(2a) and R^(2b), (ii) R^(2c) and R^(2d)        or (iii) R^(12a) and R^(12b) together with the carbon atom to        which they are attached form a (i) 3 to 7 membered carbocyclic        ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2        heteroatoms selected from N, O, and S, wherein the 3 to 7        membered carbocyclic ring or the 4 to 7 membered heterocyclic        ring is optionally substituted with one to three R^(A2), wherein        each R^(A2) is independently oxo, halo, cyano, C₁₋₆alkyl,        C₃₋₆cycloalkyl or —OR^(e);    -   R^(3a), R^(3b), R^(3c), and R^(3d) are independently H,        C₁₋₆alkyl, C₁₋₄haloalkyl, or —O—C₁₋₄alkyl; or    -   any one of (i) R^(3a) and R^(3b) or (ii) R^(3c) and R^(3d)        together with the carbon atom to which they are attached        form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7        membered heterocyclic ring containing 1 or 2 heteroatoms        selected from N, O, and S, wherein the 3 to 7 membered        carbocyclic ring or the 3 to 7 membered heterocyclic ring is        optionally substituted with one to three R^(A2), wherein each        R^(A2) is independently oxo, halo, cyano, C₁₋₆alkyl,        C₃₋₆cycloalkyl or —OR^(e);    -   R^(4a), R^(4b), R^(5a), R^(5b), R^(5c), R^(5d), R^(8a), R^(8b),        R^(9a), R^(9b), R^(9c), and R^(9d) are independently H,        C₁₋₆alkyl, C₁₋₄haloalkyl, halo, hydroxyl, cyano, —O—C₁₋₄alkyl,        or C₁₋₄alkylene-O—C₁₋₄alkyl; or    -   any one of (i) R^(4a) and R^(4b), (ii) R^(5a) and R^(5b), (iii)        R^(5c) and R^(5d), (iv) R^(5a) and R^(5c), (v) R^(5b) and        R^(5d), (vi) R^(8a) and R^(8b), (vii) R^(9a) and R^(9b), (viii)        R^(9c) and R^(9d), (ix) R^(9a) and R^(9c), (x) R^(9b) and        R^(9d), (xi) R^(8b) and one of R^(5a), R^(5b), R^(5c), R^(5d),        and R⁷, or (xii) one of R^(9a), R^(9b), R^(9c), and R^(9d) and        one of R^(4a), R^(4b), R^(5a), R^(5b), and R⁷ together with the        carbon atom to which they are attached form a (i) 3 to 7        membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic        ring containing 1 to 2 heteroatoms selected from N, O, and S,        wherein the 3 to 7 membered carbocyclic ring or the 4 to 7        membered heterocyclic ring is optionally substituted with one to        three R^(A3), wherein each R^(A3) is independently oxo, halo,        cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e);    -   each R^(6a), R^(6b), R^(10a), and R^(10b) is independently H,        halo, C₁₋₄haloalkyl, or C₁₋₄alkyl; or any one of (i) R^(6a) and        R^(6b) or (ii) R^(10a) and R^(10b) together with the carbon        atoms to which each is attached form (i) a 5 to 10 membered        carbocyclic ring, (ii) 5 to 10 membered heterocyclic ring        containing 1 or 2 heteroatom selected from N, O, and S, (iii) a        6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered        heteroaromatic ring containing 1 to 3 heteroatoms selected from        N, O and S, wherein the 5 to 10 membered carbocyclic ring, 5 to        10 membered heterocyclic ring, the 6 to 10 membered aromatic        ring, or the 5 to 10 membered heteroaromatic ring is optionally        substituted with one to four R^(A4), wherein each R^(A4) is        independently oxo, halo, cyano, C₁₋₄alkyl, C₃₋₆cycloalkyl or        —OR^(e);    -   R⁷ is H, C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, C(O)R^(c), or SO₂R^(c);    -   R¹¹ is H, C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, —C(O)—R^(a), —S(O)_(n)—R^(a), —CH₂—R^(a);    -   each R^(a) is independently (i) H, (ii) C₁₋₆alkyl, (iii)        C₃₋₆cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5        to 10 membered heterocyclic ring containing 1 or 2 heteroatom        selected from N, O, and S, (vi) a 6 to 10 membered aromatic        ring, or (iv) a 5 to 10 membered heteroaromatic ring containing        1 to 3 heteroatoms selected from N, O and S;    -   wherein the C₁₋₆alkyl, C₃₋₆cycloalkyl, 5 to 10 membered        carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10        membered aromatic ring or 5 to 10 membered heteroaromatic ring        is optionally substituted with 0 to 4 substituents independently        selected from the group consisting of (i) oxo (ii) halo, (iii)        cyano, (iv) —O—C₁₋₄alkyl, (v) C₁₋₆alkyl, (vi) —OR^(e) (vii) 3 to        10 membered carbocyclic ring, (viii) 5 to 10 membered        heterocyclic ring containing 1 or 2 heteroatom selected from N,        O, and S, (ix) 6 to 10 membered aromatic ring, or (x) a 5 to 10        membered heteroaromatic ring containing 1 to 3 heteroatoms        selected from N, O and S;        wherein the 3 to 10 membered carbocyclic ring, 5 to 10 membered        heterocyclic ring, 6 to 10 membered aromatic ring, or 5 to 10        membered heteroaromatic ring is optionally substituted with one        to four R^(A5), wherein each R^(A5) is independently oxo, halo,        cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e);    -   R^(b) is H, C₁₋₄alkyl, C₁₋₄haloalkyl or C₃₋₆cycloalkyl;    -   R^(f) is H, halo, C₁₋₄alkyl, or C₁₋₄haloalkyl;    -   each R^(c) is independently, H, C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl; C(O)R^(d), or —SO₂R^(d);    -   each R^(d) is independently C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, —NR^(e) ₂, or —OR^(e);    -   each R^(e) is independently H, C₁₋₄alkyl or C₃₋₆cycloalkyl        wherein each C₁₋₄alkyl or C₃₋₆cycloalkyl is optionally        substituted by a halo or a cyano; and    -   each n is 0, 1, or 2.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof the disclosure, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.

In another embodiment, the disclosure provides a kit comprising acompound of the disclosure, or a pharmaceutically acceptable saltthereof, and instructions for use.

In another embodiment, the disclosure provides a method of treating anHIV infection in a human having or at risk of having the infection,wherein the method comprises administering to the human atherapeutically effective amount of a compound of the disclosure, orpharmaceutically acceptable salt thereof, or the pharmaceutical of thedisclosure.

In another embodiment, the disclosure provides use of a compound of thedisclosure, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the disclosure, for treating an HIVinfection in a human having or at risk of having the infection.

In another aspect, the disclosure provides a compound of the disclosure,or pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the disclosure, for use in medical therapy.

In another embodiment, the disclosure provides use of a compound of thedisclosure, or pharmaceutically acceptable salt thereof, or apharmaceutical composition of the disclosure, for use in treating an HIVinfection.

In another aspect, the disclosure provides use of a compound of thedisclosure, or pharmaceutically acceptable salt thereof, or thepharmaceutical composition of the disclosure, in the manufacture of amedicament for treating an HIV infection in a human having or at risk ofhaving the infection.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodimentsdisclosed herein. However, one skilled in the art will understand thatthe embodiments disclosed herein may be practiced without these details.The description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the claimed subject matter, and is not intended tolimit the appended claims to the specific embodiments illustrated. Theheadings used throughout this disclosure are provided for convenienceonly and are not to be construed to limit the claims in any way.Embodiments illustrated under any heading may be combined withembodiments illustrated under any other heading.

I. Definitions

Unless the context requires otherwise, throughout the present disclosureand claims, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is as “including, but not limited to”.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment disclosed herein. Thus, the appearances of the phrases “inone embodiment” or “in an embodiment” in various places throughout thisspecification are not necessarily all referring to the same embodiment.Furthermore, the particular features, structures, or characteristics maybe combined in any suitable manner in one or more embodiments.

“Amino” refers to the —NH₂ radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Oxo” refers to the ═O substituent.

A prefix such as “C_(u-v)” or (C_(u)-C_(v)) indicates that the followinggroup has from u to v carbon atoms. For example, “C₁₋₆alkyl” indicatesthat the alkyl group has from 1 to 6 carbon atoms.

“Alkyl” refers to a straight or branched chain hydrocarbon radicalconsisting of carbon and hydrogen atoms, which is saturated, having fromone to twelve carbon atoms (C₁₋₁₂alkyl), in certain embodiments one toeight carbon atoms (C₁₋₈alkyl) or one to six carbon atoms (C₁₋₆alkyl),or one to four carbon atoms (C₁₋₄alkyl), and which is attached to therest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl,1-methylethyl (iso-propyl), n-butyl, 1-methylpropyl (sec-butyl),2-methylpropyl (iso-butyl), 1,1-dimethylethyl (t-butyl), n-pentyl,hexyl, 3-methylhexyl, 2-methylhexyl, and the like.

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent alkane. For example, an alkylene group can have 1 to20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typicalalkylene radicals include, but are not limited to, methylene (—CH₂—),1,1 ethyl (—CH(CH₃)—), 1,2-ethyl (—CH₂CH₂—), 1,1-propyl (—CH(CH₂CH₃)—),1,2-propyl (—CH₂CH(CH₃)—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl(—CH₂CH₂CH₂CH₂—), and the like.

“Aryl” or “aromatic ring” refers to an aromatic carbocyclic group havinga single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic ortricyclic) including fused systems. As used herein, aryl has 6 to 20ring carbon atoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e.,C₆₋₁₂ aryl), or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examplesof aryl groups include, but are not limited to, phenyl, naphthyl,fluorenyl, and anthryl. Aryl, however, does not encompass or overlap inany way with heteroaryl defined below.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” or “carbocyclic ring” refers to a saturated or partiallysaturated cyclic alkyl group having a single ring or multiple ringsincluding fused, bridged, and spiro ring systems.

The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclicgroup having at least one double bond). As used herein, cycloalkyl hasfrom 3 to 20 ring carbon atoms (i.e., C₃₋₂₀ cycloalkyl), 3 to 12 ringcarbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10 ring carbon atoms (i.e.,C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈ cycloalkyl), or3 to 6 ring carbon atoms (i.e., C₃₋₆ cycloalkyl). Examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.“Halocycloalkyl” refers to a cycloalkyl substituted with one or morehalogens.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl group, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike.

“Heteroaryl” or “heteroaromatic ring” refers to an aromatic group havinga single ring, multiple rings, or multiple fused rings, with one or morering heteroatoms independently selected from nitrogen, oxygen, andsulfur. As used herein, heteroaryl includes 5 to 20 ring atoms (5 to 20membered heteroaromatic ring), 5 to 12 ring atoms (5 to 12 memberedheteroaromatic ring), 5 to 10 ring atoms (5 to 10 memberedheteroaromatic ring) or 5 to 6 ring atoms (5 to 6 memberedheteroaromatic ring); and 1 to 5 ring heteroatoms, 1 to 4 ringheteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ringheteroatom independently selected from nitrogen, oxygen, and sulfur.Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl,pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does notencompass or overlap with aryl as defined above.

“Heterocyclyl” or “heterocyclic ring” refers to a non-aromatic radicalor ring having from three to fifteen atoms wherein from one to six atomsare heteroatoms selected from the group consisting of nitrogen, oxygenand sulfur and attached to the rest of the molecule by a single bond. Incertain embodiments, “heterocyclyl” has from three to ten atoms, whereinfrom one to four atoms are heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur, or from three to seven atoms,wherein from one to two atoms are heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur. The nitrogen, carbon orsulfur atoms in the heterocyclyl may be optionally oxidized; thenitrogen atom may be optionally quaternized. As used herein,“heterocyclyl” or “heterocyclic ring” refers to rings that are saturatedunless otherwise indicated, e.g., in some embodiments “heterocyclyl” or“heterocyclic ring” refers to rings that are saturated or partiallysaturated where specified. Examples of such heterocyclyl include, butare not limited to, dioxolanyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

The embodiments disclosed herein are also meant to encompass allpharmaceutically acceptable compounds of Formula I beingisotopically-labeled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. In certainembodiments, these radiolabeled compounds are useful to help determineor measure the effectiveness of the compounds, by characterizing, forexample, the site or mode of action, or binding affinity topharmacologically important site of action. Certain isotopically-labeledcompounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa,IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb,for example, those incorporating a radioactive isotope, are useful indrug and/or substrate tissue distribution studies. The radioactiveisotopes tritium, i.e., ³H, and carbon-14, i.e., ¹⁴C, are particularlyuseful for this purpose in view of their ease of incorporation and readymeans of detection.

In certain embodiments, substitution with heavier isotopes such asdeuterium, i.e., ²H, may afford certain therapeutic advantages resultingfrom greater metabolic stability. For example, in vivo half-life mayincrease or dosage requirements may be reduced. Thus, heavier isotopesmay be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O, and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of Formula I, Ia, Ib, II, IIa, IIb, III,IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIb, VIII,VIIIa, or VIIIb can be prepared by techniques known to those skilled inthe art or by processes analogous to those described in the Examples asset out below using an appropriate isotopically-labeled reagent in placeof the non-labeled reagent previously employed.

The methods, compositions, kits and articles of manufacture providedherein use or include compounds (e.g., a compound of Formula I, Ia, Ib,II, IIa, IIb, III, IIIa, IIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb,VII, VIIa, VIIb, VIII, VIIIa, or VIIIb) or pharmaceutically acceptablesalts thereof, in which from 1 to n hydrogen atoms attached to a carbonatom may be replaced by a deuterium atom or D, in which n is the numberof hydrogen atoms in the molecule. As known in the art, the deuteriumatom is a non-radioactive isotope of the hydrogen atom. Such compoundsincrease resistance to metabolism, and thus are useful for increasingthe half-life of compounds or pharmaceutically acceptable salts thereof,when administered to a mammal. See, e.g., Foster, “Deuterium IsotopeEffects in Studies of Drug Metabolism”, Trends Pharmacol. Sci.,5(12):524-527 (1984). Such compounds can be synthesized by means knownin the art, for example by employing starting materials in which one ormore hydrogen atoms have been replaced by deuterium.

The embodiments disclosed herein are also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the embodiments disclosed hereininclude compounds produced by a process comprising administering acompound according to the embodiments disclosed herein to a mammal for aperiod of time sufficient to yield a metabolic product thereof. Suchproducts are typically identified by administering a radiolabeledcompound according to the embodiments disclosed herein in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventor circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted heterocyclyl” meansthat the heterocyclyl radical may or may not be substituted and that thedescription includes both substituted heterocyclyl radicals andheterocyclyl radicals having no substitution.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,emulsifier, or other pharmacologically inactive substance that isformulated in combination with a pharmacologically active ingredient ofa pharmaceutical composition and is compatible with the otheringredients of the formulation and suitable for use in humans ordomestic animals without undue toxicity, irritation, allergic response,and the like.

Examples of “pharmaceutically acceptable salts” of the compoundsdisclosed herein include salts derived from an appropriate base, such asan alkali metal (for example, sodium), an alkaline earth metal (forexample, magnesium), ammonium and NX₄ ⁺ (wherein X is C₁₋₄alkyl).Pharmaceutically acceptable salts of a nitrogen atom or an amino groupinclude, for example, salts of organic carboxylic acids such as acetic,trifluoroacetic, adipic, ascorbic, aspartic, butyric, camphoric,cinnamic, citric, digluconic, glutamic, glycolic, glycerophosphoric,formic, hexanoic, benzoic, lactic, fumaric, tartaric, maleic,hydroxymaleic, malonic, malic, mandelic, isethionic, lactobionic,nicotinic, oxalic, pamoic, pectinic, phenylacetic, 3-phenylpropionic,pivalic, propionic, pyruvic, salicylic, stearic, sulfanilic, tartaric,undecanoic, and succinic acids; organic sulfonic acids, such asmethanesulfonic, ethanesulfonic, camphorsulfonic, mesitylenesulfonic,benzenesulfonic, p-toluenesulfonic acids, naphthalenesulfonic, and2-naphthalenesulfonic; and inorganic acids, such as hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, and sulfamic acids.Pharmaceutically acceptable salts of a compound of a hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as Na⁺ and NX₄ ⁺ (wherein X is independently selected from H or aC₁₋₄alkyl group).

For therapeutic use, salts of active ingredients of the compoundsdisclosed herein will typically be pharmaceutically acceptable, i.e.,they will be salts derived from a physiologically acceptable acid orbase. However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a compound of Formula I or another compound of theembodiments disclosed herein. All salts, whether or not derived from aphysiologically acceptable acid or base, are within the scope of theembodiments disclosed herein.

Metal salts typically are prepared by reacting the metal hydroxide witha compound according to the embodiments disclosed herein. Examples ofmetal salts which are prepared in this way are salts containing Li⁺,Na⁺, and K⁺. A less soluble metal salt can be precipitated from thesolution of a more soluble salt by addition of the suitable metalcompound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines. Finally, it is to beunderstood that the compositions herein comprise compounds disclosedherein in their un-ionized, as well as zwitterionic form.

A “pharmaceutical composition” refers to a formulation of a compound ofthe embodiments disclosed herein and a medium generally accepted in theart for the delivery of the biologically active compound to mammals,e.g., humans. Such a medium includes all pharmaceutically acceptableexcipients.

“Effective amount” or “therapeutically effective amount” refers to anamount of a compound according to the embodiments disclosed herein,which when administered to a patient in need thereof, is sufficient toeffect treatment of disease-states, conditions, or disorders disclosedherein. Such an amount would be sufficient to elicit the biological ormedical response of a tissue system, or patient that is sought by aresearcher or clinician. The amount of a compound according to theembodiments disclosed herein which constitutes a therapeuticallyeffective amount will vary depending on such factors as the compound andits biological activity, the composition used for administration, thetime of administration, the route of administration, the rate ofexcretion of the compound, the duration of the treatment, the type ofdisease-state or disorder being treated and its severity, drugs used incombination, or coincidentally, with the compounds of the embodimentsdisclosed herein, and the age, body weight, general health, sex and dietof the patient. Such a therapeutically effective amount can bedetermined by one of ordinary skill in the art having regard to theirown knowledge, the state of the art, and this disclosure.

The terms “treating” and “treatment” as used herein are intended to meanthe administration of a compound or composition according to the presentembodiments disclosed herein to alleviate or eliminate one or moresymptoms of HIV infection and/or to reduce viral load in a patient. Incertain embodiments, the terms “treating” and “treatment” also encompassthe administration of a compound or composition according to the presentembodiments disclosed herein post-exposure of the individual to thevirus but before the appearance of symptoms of the disease, and/or priorto the detection of the virus in the blood, to prevent the appearance ofsymptoms of the disease and/or to prevent the virus from reachingdetectable levels in the blood, and the administration of a compound orcomposition according to the present embodiments disclosed herein toprevent perinatal transmission of HIV from mother to baby, byadministration to the mother before giving birth and to the child withinthe first days of life. The terms “treating” and “treatment” alsoencompass the administration of a compound or composition according tothe present embodiments disclosed herein before the exposure of theindividual to the virus (also called pre-exposure prophylaxis or PrEP),to prevent HIV infection from taking hold if the individual is exposedto the virus and/or to keep the virus from establishing a permanentinfection and/or to prevent the appearance of symptoms of the diseaseand/or to prevent the virus from reaching detectable levels in theblood. The terms “treating” and “treatment” also encompass theadministration of a compound or composition according to the presentembodiments disclosed herein both before and after the exposure of theindividual to the virus.

As used herein, the terms “preventing” and “prevention” refer to theadministration of a compound, composition, or pharmaceutically saltaccording to the present disclosure pre- or post-exposure of the humanto the virus but before the appearance of symptoms of the disease,and/or prior to the detection of the virus in the blood. The terms alsorefer to prevention of the appearance of symptoms of the disease and/orto prevent the virus from reaching detectible levels in the blood. Theterms include both pre-exposure prophylaxis (PrEP), as well aspost-exposure prophylaxis (PEP) and event driven or “on demand”prophylaxis. The terms also refer to prevention of perinataltransmission of HIV from mother to baby, by administration to the motherbefore giving birth and to the child within the first days of life. Theterms also refer to prevention of transmission of HIV through bloodtransfusion.

The term “antiviral agent” as used herein is intended to mean an agent(compound or biological) that is effective to inhibit the formationand/or replication of a virus in a human being, including but notlimited to agents that interfere with either host or viral mechanismsnecessary for the formation and/or replication of a virus in a humanbeing.

The term “inhibitor of HIV replication” as used herein is intended tomean an agent capable of reducing or eliminating the ability of HIV toreplicate in a host cell, whether in vitro, ex vivo or in vivo.

The compounds of the embodiments disclosed herein, or theirpharmaceutically acceptable salts may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.The present disclosure is meant to include all such possible isomers, aswell as their racemic, scalemic, and optically pure forms. Opticallyactive (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingmethods such as chromatography and fractional crystallization.Techniques for the preparation/solation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are non-superimposablemirror images of one another. In any of the embodiments disclosedherein, compounds disclosed herein may be in the form of a stereoisomerthereof.

“Partially unsaturated” refers to a cyclic group which contains at leastone double bond but is not aromatic.

II. Compounds

Disclosed herein are compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is a H, C₆₋₁₀aryl or C₆₋₁₀heteroaryl, wherein the C₆₋₁₀aryl        or C₆₋₁₀heteroaryl is optionally substituted with one to four        R^(A1), wherein each R^(A1) is independently halo, C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl, or        C₁₋₄alkyl-O—C₁₋₄alkyl;    -   Y is selected from the group consisting of —C(O)NH—,

-   -   L is —CR^(3a)R^(3b)—, —C(O)—, —SO₂—,        —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, or —N(R^(a))—;    -   W¹ is a bond or —CR^(4a)R^(4b)—;    -   W² is —CR^(5a)R^(5b)—, —CR^(5a)R^(5b)CR^(5c)R^(5d)—,        —CR^(6a)═CR^(6b)—, —N(R⁷)—, —O—, —S(O)_(n)—, —C(O)NR^(e)—,        —CR^(5a)R^(5b)—N(R⁷)—, —CR^(5a)R^(5b)—O—,        —CR^(5a)R^(5b)—S(O)_(n)—, —CR^(5a)R^(5b)—C(O)NR^(e)—, or        —CR^(5a)R^(5b)—NR^(e)—C(O)—; —S(O)_(n)N(R^(e))—CR^(5a)R^(5b)—,        —N(R^(e))—S(O)_(n)—CR^(5a)R^(5b)—, —N(R^(e))—C(O)—CR^(5a)R^(5b)—        or —CR^(5a)R^(5b)—NR^(e)—C(O)—;    -   X is a bond or —CR^(8a)R^(8b)—;    -   Z is —CR^(9a)R^(9b)—, —CR^(9a)R^(9b)CR^(9c)R^(9d)—, or        —CR^(10a)═CR^(10b)—;    -   T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d) and U is        —NR¹¹—, —CR^(12a)R^(12b)—, —S(O)_(n)—, —C(O)—, or —O—; or T and        U together are

-   -   R^(2a), R^(2b), R^(2c), R^(2d), R^(12a), and R^(12b) are        independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),        —CH₂—S(O)_(n)R^(a)—, —OR^(a), —C(O)—NHR^(a), —NHR^(a)—,        —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,        —S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or    -   any one of (i) R^(2a) and R^(2b), (ii) R^(2c) and R^(2d)        or (iii) R^(12a) and R^(12b) together with the carbon atom to        which they are attached form (i) a 3 to 7 membered carbocyclic        ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or        2 heteroatoms selected from N, O, and S, wherein the 3 to 7        membered carbocyclic ring or the 4 to 7 membered heterocyclic        ring is optionally substituted with one to three R^(A2), wherein        each R^(A2) is independently oxo, halo, cyano, C₁₋₆alkyl,        C₃₋₆cycloalkyl or —OR^(e);    -   R^(3a) and R^(3b) are independently H, C₁₋₆-alkyl,        C₁₋₄haloalkyl, or —O—C₁₋₄alkyl; or    -   any one of (i) R^(3a) and R^(3b) or (ii) R^(3c) and R^(3d)        together with the carbon atom to which they are attached        form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7        membered heterocyclic ring containing 1 or 2 heteroatoms        selected from N, O, and S, wherein the 3 to 7 membered        carbocyclic ring or the 3 to 7 membered heterocyclic ring is        optionally substituted with one to three R^(A2), wherein each        R^(A2) is independently oxo, halo, cyano, C₁₋₆alkyl,        C₃₋₆cycloalkyl or —OR^(e);    -   R^(4a), R^(4b), R^(5a), R^(5b), R^(5c), R^(5d), R^(8a), R^(8b),        R^(9a), R^(9b), R^(9c), and R^(9d) are independently H,        C₁₋₆alkyl, C₁₋₄haloalkyl, halo, hydroxyl, cyano, —O—C₁₋₄alkyl,        or C₁₋₄alkylene-O—C₁₋₄alkyl; or    -   any one of (i) R^(4a) and R^(4b), (ii) R^(5a) and R^(5b), (iii)        R^(5c) and R^(5d), (iv) R^(5a) and R^(5c), (v) R^(5b) and        R^(5d), (vi) R^(8a) and R^(8b), (vii) R^(9a) and R^(9b), (viii)        R^(9c) and R^(9d), (ix) R^(9a) and R^(9c), (x) R^(9b) and        R^(9d), (xi) R^(8b) and one of R^(5a), R^(5b), R^(5c), R^(5d),        and R⁷, or (xii) one of R^(9a), R^(9b), R^(9c), and R^(9d) and        one of R^(4a), R^(4b), R^(5a), R^(5b), and R⁷ together with the        carbon atom to which they are attached form (i) a 3 to 7        membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic        ring containing 0 to 2 heteroatoms selected from N, O, and S,        wherein the 3 to 7 membered carbocyclic ring or the 4 to 7        membered heterocyclic ring is optionally substituted with one to        three R^(A3), wherein each R^(A3) is independently oxo, halo,        cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e);    -   each R^(6a), R^(6b), R^(10a), and R^(10b) is independently H,        halo, C₁₋₄haloalkyl, or C₁₋₆alkyl; or    -   any one of (i) R^(6a) and R^(6b) or (ii) R^(10a) and R^(10b)        together with the carbon atoms to which each is attached        form (i) a 5 to 10 membered carbocyclic ring, (ii) 5 to 10        membered heterocyclic ring containing 1 or 2 heteroatom selected        from N, O, and S, (iii) a 6 to 10 membered aromatic ring,        or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3        heteroatoms selected from N, O and S, wherein the 5 to 10        membered carbocyclic ring, 5 to 10 membered heterocyclic ring,        the 6 to 10 membered aromatic ring, or the 5 to 10 membered        heteroaromatic ring is optionally substituted with one to four        R^(A4), wherein each R^(A4) is independently oxo, halo, cyano,        C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e);    -   R⁷ is H, C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, C(O)R^(c), or SO₂R^(c);    -   R¹¹ is H, C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, —C(O)—R^(a), —S(O)_(n)—R^(a), —CH₂—R^(a);    -   each R^(a) is independently (i) H, (ii) C₁₋₆alkyl, (iii)        C₃₋₆cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5        to 10 membered heterocyclic ring containing 1 or 2 heteroatom        selected from N, O, and S, (vi) a 6 to 10 membered aromatic        ring, or (iv) a 5 to 10 membered heteroaromatic ring containing        1 to 3 heteroatoms selected from N, O and S; wherein the        C₁₋₆alkyl, C₃₋₆cycloalkyl, 5 to 10 membered carbocyclic ring, 5        to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring        or the 5 to 10 membered heteroaromatic ring is optionally        substituted with 0 to 4 substituents independently selected from        the group consisting of (i) oxo (ii) halo, (iii) cyano, (iv)        —O—C₁₋₄alkyl, (v) C₁₋₆alkyl, (vi) —OR^(e) (vii) 3 to 10 membered        carbocyclic ring, (viii) 5 to 10 membered heterocyclic ring        containing 1 or 2 heteroatom selected from N, O, and S, (ix) 6        to 10 membered aromatic ring, or (x) a 5 to 10 membered        heteroaromatic ring containing 1 to 3 heteroatoms selected from        N, O and S; wherein the 3 to 10 membered carbocyclic ring, 5 to        10 membered heterocyclic ring, 6 to 10 membered aromatic ring,        or 5 to 10 membered heteroaromatic ring is optionally        substituted with one to four R^(A5), wherein each R^(A5) is        independently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or        —OR^(e);    -   R^(b) is H, C₁₋₄alkyl, C₁₋₄haloalkyl or C₃₋₆cycloalkyl;    -   R^(f) is H, halo, C₁₋₄alkyl, or C₁₋₄haloalkyl;    -   each R^(c) is independently, H, C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, C(O)R^(d), or —SO₂R^(d);    -   each R^(d) is independently C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, —NR^(e) ₂, or —OR^(e);    -   each R^(e) is independently H, C₁₋₄alkyl or C₃₋₆cycloalkyl        wherein each C₁₋₄alkyl or C₃₋₆cycloalkyl is optionally        substituted by a halo or a cyano; and    -   each n is 0, 1, or 2.

In some embodiments, of the compounds of Formula I, R¹ is H, C₆₋₁₀arylor C₆₋₁₀heteroaryl, wherein the C₆₋₁₀aryl or C₆₋₁₀heteroaryl areoptionally substituted with one to four R^(A1), wherein each R^(A1) isindependently halo, C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano,—O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl, or C₁₋₄alkyl-O—C₁₋₄alkyl;

-   -   Y is selected from the group consisting of —C(O)NH—,

-   -   L is —CR^(3a)R^(3b)—, —C(O)—, —SO₂—,        —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, or —N(R^(a))—;    -   W¹ is a bond or —CR^(4a)R^(4b)—;    -   W² is —CR^(5a)R^(5b)—, —CR^(5a)R^(5b)CR^(5c)R^(5d)—,        —CR^(6a)═CR^(6b)—, —N(R⁷)—, —O—, —S(O)_(n)—, —C(O)NR^(e)—,        —CR^(5a)R^(5b)—N(R⁷)—, —CR^(5a)R^(5b)—O—,        —CR^(5a)R^(5b)—S(O)_(n)—, —CR^(5a)R^(5b)—C(O)NR^(e)—,        —CR^(5a)R^(5b)—NR^(e)—C(O)—, —S(O)_(n)N(R^(e))—CR^(5a)R^(5b)—,        or —N(R^(e))—S(O)_(n)—CR^(5a)R^(5b)—;    -   X is a bond or —CR^(8a)R^(8b)—;    -   Z is —CR^(9a)R^(9b)—, —CR^(9a)R^(9b)CR^(9c)R^(9d)—, or        —CR^(10a)═CR^(10b)—;    -   T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); U is        —NR¹¹—, —CR^(12a)R^(12b)—, —S(O)_(n)—, —C(O)—, or —O—; or T and        U together are

-   -   R^(2a), R^(2b), R^(2c), R^(2d), R^(12a), and R^(12b) are        independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),        —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NHR^(a),        —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,        —S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or    -   any one of (i) R^(2a) and R^(2b), (ii) R^(2c) and R^(2d)        or (iii) R^(12a) and R^(12b) together with the carbon atom to        which they are attached form a (i) 3 to 7 membered carbocyclic        ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2        heteroatoms selected from N, O, and S, wherein the 3 to 7        membered carbocyclic ring or the 4 to 7 membered heterocyclic        ring is optionally substituted with one to three R^(A2), wherein        each R^(A2) is independently oxo, halo, cyano, C₁₋₆alkyl,        C₃₋₆cycloalkyl or —OR^(e);    -   R^(3a), R^(3b), R^(3c), and R^(3d) are independently H,        C₁₋₆-alkyl, C₁₋₄haloalkyl, or —O—C₁₋₄alkyl;    -   R^(4a), R^(4b), R^(5a), R^(5b), R^(5c), R^(5d), R^(8a), R^(8b),        R^(9a), R^(9b), R^(9c), and R^(9d) are independently H,        C₁₋₆-alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl,        halo, hydroxyl, cyano, —O—C₁₋₄alkyl, or        C₁₋₄alkylene-O—C₁₋₄alkyl;    -   each R^(6a), R^(6b), R^(10a), and R^(10b) is independently H,        halo, C₁₋₄haloalkyl, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆-alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, C(O)R^(c), or SO₂R^(c);    -   R¹¹ is H, C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, —C(O)—R^(a), —S(O)_(n)—R^(a), —CH₂—R^(a);    -   each R^(a) is independently (i) H, (ii) C₁₋₆alkyl, (iii)        C₃₋₆cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5        to 10 membered heterocyclic ring containing 1 or 2 heteroatom        selected from N, O, and S, (vi) a 6 to 10 membered aromatic        ring, or (iv) a 5 to 10 membered heteroaromatic ring containing        1 to 3 heteroatoms selected from N, O and S;    -   wherein the C₁₋₆alkyl, C₃₋₆cycloalkyl, 5 to 10 membered        carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10        membered aromatic ring or 5 to 10 membered heteroaromatic ring        is optionally substituted with 0 to 4 substituents independently        selected from the group consisting of (i) oxo (ii) halo, (iii)        cyano, (iv) —O—C₁₋₄alkyl, (v) C₁₋₆alkyl, (vi) —OR^(e) (vii) 3 to        10 membered carbocyclic ring, (viii) 5 to 10 membered        heterocyclic ring containing 1 or 2 heteroatom selected from N,        O, and S, (ix) 6 to 10 membered aromatic ring, or (x) a 5 to 10        membered heteroaromatic ring containing 1 to 3 heteroatoms        selected from N, O and S; wherein the 3 to 10 membered        carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10        membered aromatic ring, or 5 to 10 membered heteroaromatic ring        is optionally substituted with one to four R^(A5), wherein each        R^(A5) is independently oxo, halo, cyano, C₁₋₆alkyl,        C₃₋₆cycloalkyl or —OR^(e);    -   R^(b) is H, C₁₋₆alkyl, C₁₋₄haloalkyl or C₃₋₆cycloalkyl;    -   R^(f) is H, halo, C₁₋₄alkyl, or C₁₋₄haloalkyl;    -   each R^(c) is independently, H, C₁₋₆alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl; C(O)R^(d), or —SO₂R^(d);    -   each R^(d) is independently C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, —NR^(e) ₂, or —OR^(e);    -   each R^(e) is independently H, C₁₋₆alkyl or C₃₋₆cycloalkyl        wherein each C₁₋₄alkyl or C₃₋₆cycloalkyl is optionally        substituted by a halo or a cyano; and    -   each n is 0, 1, or 2.

In some embodiments, of the compounds of Formula I:

-   -   R¹ is H, C₆₋₁₀aryl or C₆₋₁₀heteroaryl, wherein the C₆₋₁₀aryl or        C₆₋₁₀heteroaryl are optionally substituted with one to four        R^(A1), wherein each R^(A1) is independently halo, C₁₋₆alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl,        —O—C₃₋₆cycloalkyl, or C₁₋₄alkyl-O—C₁₋₄alkyl;    -   Y is selected from the group consisting of —C(O)NH—,

-   -   L is —CR^(3a)R^(3b)—, —C(O)—, —SO₂—,        —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, or —N(R^(a))—;    -   W¹ is a bond or —CR^(4a)R^(4b)—;    -   W² is —CR^(5a)R^(5b)—, —CR^(5a)R^(5b)CR^(5c)R^(5d)—,        —CR^(6a)═CR^(6b)—, —N(R⁷)—, —O—, —S(O)_(n)—, —C(O)NR^(e)—,        —CR^(5a)R^(5b)—N(R⁷)—, —CR^(5a)R^(5b)—O—,        —CR^(5a)R^(5b)—S(O)_(n)—, —CR^(5a)R^(5b)—C(O)NR^(e)—,        —CR^(5a)R^(5b)—NR^(e)—C(O)—, —S(O)_(n)N(R^(e))—CR^(5a)R^(5b)—,        or —N(R^(e))—S(O)_(n)—CR^(5a)R^(5b)—;    -   X is a bond or —CR^(8a)R^(8b)—;    -   Z is —CR^(9a)R^(9b)—, —CR^(9a)R^(9b)CR^(9c)R^(9d)—, or        —CR^(10a)═CR^(10b)—;    -   T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); U is        —NR¹¹—, —CR^(12a)R^(12b)—, —S(O)_(n)—, —C(O)—, or —O—; or T and        U together are

-   -   R^(2a), R^(2b), R^(2c), R^(2d), R^(12a), and R^(12b) are        independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),        —CH₂—S(O)_(n)R^(a)—, —OR^(a), —C(O)—NHR^(a), —NHR^(a)—,        —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,        —S(O)_(n)—NH(R^(e))—, or —S(O)_(n)—R^(a)—;    -   R^(3a), R^(3b), R^(3c), and R^(3d) are independently H,        C₁₋₆-alkyl, C₁₋₄haloalkyl, or —O—C₁₋₄alkyl; or    -   any one of (i) R^(3a) and R^(3b) or (ii) R^(3c) and R^(3d)        together with the carbon atom to which they are attached        form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7        membered heterocyclic ring containing 1 or 2 heteroatoms        selected from N, O, and S, wherein the 3 to 7 membered        carbocyclic ring or the 3 to 7 membered heterocyclic ring is        optionally substituted with one to three R^(A2), wherein each        R^(A2) is independently oxo, halo, cyano, C₁₋₆alkyl,        C₃₋₆cycloalkyl or —OR^(e);    -   R^(4a), R^(4b), R^(5a), R^(5b), R^(5c), R^(5d), R^(8a), R^(8b),        R^(9a), R^(9b), R^(9c), and R^(9d) are independently H,        C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl,        halo, hydroxyl, cyano, —O—C₁₋₄alkyl, or        C₁₋₄alkylene-O—C₁₋₄alkyl;    -   each R^(6a), R^(6b), R^(10a), and R^(10b) is independently H,        halo, C₁₋₄haloalkyl, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆-alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, C(O)R^(c), or SO₂R^(c);    -   R¹¹ is H, C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, —C(O)—R^(a), —S(O)_(n)—R^(a), —CH₂—R^(a);    -   each R^(a) is independently (i) H, (ii) C₁₋₆alkyl, (iii)        C₃₋₆cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5        to 10 membered heterocyclic ring containing 1 or 2 heteroatom        selected from N, O, and S, (vi) a 6 to 10 membered aromatic        ring, or (iv) a 5 to 10 membered heteroaromatic ring containing        1 to 3 heteroatoms selected from N, O and S;    -   wherein the C₁₋₆alkyl, C₃₋₆cycloalkyl, 5 to 10 membered        carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10        membered aromatic ring or 5 to 10 membered heteroaromatic ring        is optionally substituted with 0 to 4 substituents independently        selected from the group consisting of (i) oxo (ii) halo, (iii)        cyano, (iv) —O—C₁₋₄alkyl, (v) C₁₋₆alkyl, (vi) —OR^(e) (vii) 3 to        10 membered carbocyclic ring, (viii) 5 to 10 membered        heterocyclic ring containing 1 or 2 heteroatom selected from N,        O, and S, (ix) 6 to 10 membered aromatic ring, or (x) a 5 to 10        membered heteroaromatic ring containing 1 to 3 heteroatoms        selected from N, O and S; wherein the 3 to 10 membered        carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10        membered aromatic ring, or 5 to 10 membered heteroaromatic ring        is optionally substituted with one to four R^(A5), wherein each        R^(A5) is independently oxo, halo, cyano, C₁₋₆alkyl,        C₃₋₆cycloalkyl or —OR^(e);    -   R^(b) is H, C₁₋₆alkyl, C₁₋₄haloalkyl or C₃₋₆cycloalkyl;    -   R^(f) is H, halo, C₁₋₆alkyl, or C₁₋₄haloalkyl;    -   each R^(c) is independently, H, C₁₋₆alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl; C(O)R^(d), or —SO₂R^(d);    -   each R^(d) is independently C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, —NR^(e) ₂, or —OR^(e);    -   each R^(e) is independently H, C₁₋₆alkyl or C₃₋₆cycloalkyl        wherein each C₁₋₄alkyl or C₃₋₆cycloalkyl is optionally        substituted by a halo or a cyano; and    -   each n is 0, 1, or 2.

In some embodiments, of the compounds of Formula I:

-   -   R¹ is H, C₆₋₁₀aryl or C₆₋₁₀heteroaryl, wherein the C₆₋₁₀aryl or        C₆₋₁₀heteroaryl are optionally substituted with one to four        R^(A1), wherein each R^(A1) is independently halo, C₁₋₆alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl,        —O—C₃₋₆cycloalkyl, or C₁₋₄alkyl-O—C₁₋₄alkyl;    -   Y is selected from the group consisting of —C(O)NH—,

-   -   L is —CR^(3a)R^(3b)—, —C(O)—, —SO₂—,        —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, or —N(R^(a))—;    -   W¹ is a bond or —CR^(4a)R^(4b)—;    -   W² is —CR^(5a)R^(5b)—, —CR^(5a)R^(5b)CR^(5c)R^(5d)—,        —CR^(6a)═CR^(6b)—, —N(R⁷)—, —O—, —S(O)_(n)—, —C(O)NR^(e)—,        —CR^(5a)R^(5b)—N(R⁷)—, —CR^(5a)R^(5b)—O—,        —CR^(5a)R^(5b)—S(O)_(n)—, —CR^(5a)R^(5b)—C(O)NR^(e)—,        —CR^(5a)R^(5b)—NR^(e)—C(O)—, —S(O)_(n)N(R^(e))—CR^(5a)R^(5b)—,        or —N(R^(e))—S(O)_(n)—CR^(5a)R^(5b)—;    -   X is a bond or —CR^(8a)R^(8b)—;    -   Z is —CR^(9a)R^(9b)—, —CR^(9a)R^(9b)CR^(9c)R^(9d)—, or        —CR^(10a)═CR^(10b)—;    -   T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); U is        —NR¹¹—, —CR^(12a)R^(12b)—, —S(O)_(n)—, —C(O)—, or —O—; or T and        U together are

-   -   R^(2a), R^(2b), R^(2c), R^(2d), R^(12a), and R^(12b) are        independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),        —CH₂—S(O)_(n)R^(a)—, —OR^(a), —C(O)—NHR^(a), —NHR^(a)—,        —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)— —NR^(e)—S(O)_(n)R^(a)—,        —S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or    -   R^(3a), R^(3b), R^(3c), and R^(3d) are independently H,        C₁₋₆-alkyl, C₁₋₄haloalkyl, or —O—C₁₋₄alkyl; or    -   R^(4a), R^(4b), R^(5a), R^(5b), R^(5c), R^(5d), R^(8a), R^(8b),        R^(9a), R^(9b), R^(9c), and R^(9d) are independently H,        C₁₋₆-alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl,        halo, hydroxyl, cyano, —O—C₁₋₄alkyl, or        C₁₋₄alkylene-O—C₁₋₄alkyl; or    -   any one of (i) R^(4a) and R^(4b), (ii) R^(5a) and R^(5b), (iii)        R^(5c) and R^(5d), (iv) R^(5a) and R^(5c), (v) R^(5b) and        R^(5d), (vi) R^(8a) and R^(8b), (vii) R^(9a) and R^(9b), (viii)        R^(9c) and R^(9d), (ix) R^(9a) and R^(9c), (x) R^(9b) and        R^(9d), (xi) R^(8b) and one of R^(5a), R^(5b), R^(5c), R^(5d),        and R⁷, or (x) one of R^(9a), R^(9b), R^(9c), and R^(9d) and one        of R^(4a), R^(4b), R^(5a), R^(5b), and R⁷ together with the        carbon atom to which they are attached form a (i) 3 to 7        membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic        ring containing 1 to 2 heteroatoms selected from N, O, and S,        wherein the 3 to 7 membered carbocyclic ring or the 4 to 7        membered heterocyclic ring is optionally substituted with one to        three R^(A3), wherein each R^(A3) is independently oxo, halo,        cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e);    -   each R^(6a), R^(6b), R^(10a), and R^(10b) is independently H,        halo, C₁₋₄haloalkyl, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆-alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, C(O)R^(c), or SO₂R^(c);    -   R¹¹ is H, C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, —C(O)—R^(a), —S(O)_(n)—R^(a), —CH₂—R^(a);    -   each R^(a) is independently (i) H, (ii) C₁₋₆alkyl, (iii)        C₃₋₆cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5        to 10 membered heterocyclic ring containing 1 or 2 heteroatom        selected from N, O, and S, (vi) a 6 to 10 membered aromatic        ring, or (iv) a 5 to 10 membered heteroaromatic ring containing        1 to 3 heteroatoms selected from N, O and S;    -   wherein the C₁₋₆alkyl, C₃₋₆cycloalkyl, 5 to 10 membered        carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10        membered aromatic ring or 5 to 10 membered heteroaromatic ring        is optionally substituted with 0 to 4 substituents independently        selected from the group consisting of (i) oxo (ii) halo, (iii)        cyano, (iv) —O—C₁₋₄alkyl, (v) C₁₋₆alkyl, (vi) —OR^(e) (vii) 3 to        10 membered carbocyclic ring, (viii) 5 to 10 membered        heterocyclic ring containing 1 or 2 heteroatom selected from N,        O, and S, (ix) 6 to 10 membered aromatic ring, or (x) a 5 to 10        membered heteroaromatic ring containing 1 to 3 heteroatoms        selected from N, O and S; wherein the 3 to 10 membered        carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10        membered aromatic ring, or 5 to 10 membered heteroaromatic ring        is optionally substituted with one to four R^(A5), wherein each        R^(A5) is independently oxo, halo, cyano, C₁₋₆alkyl,        C₃₋₆cycloalkyl or —OR^(e);    -   R^(b) is H, C₁₋₆alkyl, C₁₋₄haloalkyl or C₃₋₆cycloalkyl;    -   R^(f) is H, halo, C₁₋₄alkyl, or C₁₋₄haloalkyl;    -   each R^(c) is independently, H, C₁₋₆alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl; C(O)R^(d), or —SO₂R^(d);    -   each R^(d) is independently C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, —NR^(e) ₂, or —OR^(e);    -   each R^(e) is independently H, C₁₋₆alkyl or C₃₋₆cycloalkyl        wherein each C₁₋₄alkyl or C₃₋₆cycloalkyl is optionally        substituted by a halo or a cyano; and    -   each n is 0, 1, or 2.

In some embodiments, of the compounds of Formula I:

-   -   R¹ is H, C₆₋₁₀aryl or C₆₋₁₀heteroaryl, wherein the C₆₋₁₀aryl or        C₆₋₁₀heteroaryl are optionally substituted with one to four        R^(A1), wherein each R^(A1) is independently halo, C₁₋₆alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl,        —O—C₃₋₆cycloalkyl, or C₁₋₄alkyl-O—C₁₋₄alkyl;    -   Y is selected from the group consisting of —C(O)NH—,

-   -   L is —CR^(3a)R^(3b)—, —C(O)—, —SO₂—,        —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, or —N(R^(a))—;    -   W¹ is a bond or —CR^(4a)R^(4b)—;    -   W² is —CR^(5a)R^(5b)—, —CR^(5a)R^(5b)CR^(5c)R^(5d)—,        —CR^(6a)═CR^(6b)—, —N(R⁷)—, —O—, —S(O)_(n)—, —C(O)NR^(e)—,        —CR^(5a)R^(5b)—N(R⁷)—, —CR^(5a)R^(5b)—O—,        —CR^(5a)R^(5b)—S(O)_(n)—, —CR^(5a)R^(5b)—C(O)NR^(e)—,        —CR^(5a)R^(5b)—NR^(e)—C(O)—, —S(O)_(n)N(R^(e))—CR^(5a)R^(5b)—,        or —N(R^(e))—S(O)_(n)—CR^(5a)R^(5b)—;    -   X is a bond or —CR^(8a)R^(8b)—;    -   Z is —CR^(9a)R^(9b)—, —CR^(9a)R^(9b)CR^(9c)R^(9d)—, or        —CR^(10a)═CR^(10b)—;    -   T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); U is        —NR¹¹—, —CR^(12a)R^(12b)—, —S(O)_(n)—, —C(O)—, or —O—; or T and        U together are

-   -   R^(2a), R^(2b), R^(2c), R^(2d), R^(12a), and R^(12b) are        independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),        —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NHR^(a),        —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)— —NR^(e)—S(O)_(n)R^(a)—,        —S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—;    -   R^(3a), R^(3b), R^(3c), and R^(3d) are independently H,        C₁₋₆-alkyl, C₁₋₄haloalkyl, or —O—C₁₋₄alkyl; R^(4a), R^(4b),        R^(5a), R^(5b), R^(5c), R^(5d), R^(8a), R^(8b), R^(9a), R^(9b),        R^(9c), and R^(9d) are independently H, C₁₋₆-alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo,        hydroxyl, cyano, —O—C₁₋₄alkyl, or C₁₋₄alkylene-O—C₁₋₄alkyl;    -   each R^(6a), R^(6b), R^(10a), and R^(10b) is independently H,        halo, C₁₋₄haloalkyl, or C₁₋₄alkyl; or    -   any one of (i) R^(6a) and R^(6b) or (ii) R^(10a) and R^(10b)        together with the carbon atoms to which each is attached        form (i) a 5 to 10 membered carbocyclic ring, (ii) 5 to 10        membered heterocyclic ring containing 1 or 2 heteroatom selected        from N, O, and S, (iii) a 6 to 10 membered aromatic ring,        or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3        heteroatoms selected from N, O and S, wherein the 5 to 10        membered carbocyclic ring, 5 to 10 membered heterocyclic ring,        the 6 to 10 membered aromatic ring, or the 5 to 10 membered        heteroaromatic ring is optionally substituted with one to four        R^(A4), wherein each R^(A4) is independently oxo, halo, cyano,        C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e);    -   R⁷ is H, C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, C(O)R^(c), or SO₂R^(c);    -   R¹¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₃₋₆halocycloalkyl, —C(O)—R^(a), —S(O)_(n)—R^(a), —CH₂—R^(a);    -   each R^(a) is independently (i) H, (ii) C₁₋₆alkyl, (iii)        C₃₋₆cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5        to 10 membered heterocyclic ring containing 1 or 2 heteroatom        selected from N, O, and S, (vi) a 6 to 10 membered aromatic        ring, or (iv) a 5 to 10 membered heteroaromatic ring containing        1 to 3 heteroatoms selected from N, O and S;    -   wherein the C₁₋₆alkyl, C₃₋₆cycloalkyl, 5 to 10 membered        carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10        membered aromatic ring or 5 to 10 membered heteroaromatic ring        is optionally substituted with 0 to 4 substituents independently        selected from the group consisting of (i) oxo (ii) halo, (iii)        cyano, (iv) —O—C₁₋₄alkyl, (v) C₁₋₆alkyl, (vi) —OR^(e) (vii) 3 to        10 membered carbocyclic ring, (viii) 5 to 10 membered        heterocyclic ring containing 1 or 2 heteroatom selected from N,        O, and S, (ix) 6 to 10 membered aromatic ring, or (x) a 5 to 10        membered heteroaromatic ring containing 1 to 3 heteroatoms        selected from N, O and S; wherein the 3 to 10 membered        carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10        membered aromatic ring, or 5 to 10 membered heteroaromatic ring        is optionally substituted with one to four R^(A5), wherein each        R^(A5) is independently oxo, halo, cyano, C₁₋₆alkyl,        C₃₋₆cycloalkyl or —OR^(e);    -   R^(b) is H, C₁₋₆alkyl, C₁₋₄haloalkyl or C₃₋₆cycloalkyl;    -   R^(f) is H, halo, C₁₋₄alkyl, or C₁₋₄haloalkyl;    -   each R^(c) is independently, H, C₁₋₆alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl; C(O)R^(d), or —SO₂R^(d);    -   each R^(d) is independently C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, —NR^(e) ₂, or —OR^(e);    -   each R^(e) is independently H, C₁₋₆alkyl or C₃₋₆cycloalkyl        wherein each C₁₋₆alkyl or C₃₋₆cycloalkyl is optionally        substituted by a halo or a cyano; and    -   each n is 0, 1, or 2.

In some embodiments, the compound of Formula I is a compound of FormulaIa:

In some embodiments, the compound of Formula I is a compound of FormulaIb:

In some embodiments for the compound of Formula I, Ia, or Ib, Y isselected from the group consisting of —C(O)NH—,

In some embodiments for the compounds of Formula I, Ia, or Ib, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, for the compounds of Formula I, Ia, or Ib, Y is—CONH—.

In some embodiments, the compound of Formula I is a compound of FormulaII:

In some embodiments, the compound of Formula I, Ia, or II is a compoundof Formula IIa:

In some embodiments, the compound of Formula I, Ib, or II is a compoundof Formula IIb:

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein eachR^(2a), R^(2b), R^(2c), and R^(2d) is independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a),—NHR^(a)—, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or any one of (i) R^(2a) andR^(2b) or (ii) R^(2c) and R^(2d) together with the carbon atom to whichthey are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selectedfrom N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4to 7 membered heterocyclic ring is optionally substituted with one tothree R^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein eachR^(2a), R^(2b), R^(2c), and R^(2d) is independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a),—NHR^(a)—, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a); or any one of (i) R^(2a) andR^(2b) or (ii) R^(2c) and R^(2d) together with the carbon atom to whichthey are attached form a 3 to 7 membered carbocyclic ring, wherein the 3to 7 membered carbocyclic ring is optionally substituted with one tothree R^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b) or —CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein eachR^(2a), R^(2b), R^(2c), and R^(2d) is independently H, C₁₋₆alkyl,C₁₋₆haloalkyl C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a),—NHR^(a)—, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or any one of (i) R^(2a) andR^(2b) or (ii) R^(2c) and R^(2d) together with the carbon atom to whichthey are attached form a 3 to 5 membered carbocyclic ring, wherein the 3to 5 membered carbocyclic ring is optionally substituted with one tothree R^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein eachR^(2a), R^(2b), R^(2c), and R^(2d) is independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a),—NHR^(a)—, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or any one of (i) R^(2a) andR^(2b) or (ii) R^(2c) and R^(2d) together with the carbon atom to whichthey are attached form a 3 membered carbocyclic ring, wherein the 3membered carbocyclic ring is optionally substituted with one to threeR^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein eachR^(2a), R^(2b), R^(2c), and R^(2d) is independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a),—NHR^(a)—, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or any one of (i) R^(2a) andR^(2b) or (ii) R^(2c) and R^(2d) together with the carbon atom to whichthey are attached form a 3 membered carbocyclic ring.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein eachR^(2a), R^(2b), R^(2c), and R^(2d) is independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a),—NHR^(a)—, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or any one of (i) R^(2a) andR^(2b) or (ii) R^(2c) and R^(2d) together with the carbon atom to whichthey are attached form a 4 to 7 membered heterocyclic ring containing 1or 2 heteroatoms selected from N, O, and S, wherein the 4 to 7 memberedheterocyclic ring is optionally substituted with one to three R^(A2),wherein each R^(A2) is independently oxo, halo, cyano, C₁₋₆alkyl,C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein eachR^(2a), R^(2b), R^(2c), and R^(2d) is independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a),—NHR^(a)—, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; In some embodiments, T is—CR^(2a)R^(2b)— or —CR^(2a)R^(2b)CR^(2c)R^(2d); wherein each R^(2a),R^(2b), R^(2c), and R^(2d) is independently H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),—OR^(a), —O—C(O)—NHR^(a), —NHR^(a)—, —C(O)—NH(R^(a))—, or—NR^(e)—C(O)R^(a)—; In some embodiments, T is —CR^(2a)R^(2b)— or—CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein each R^(2a), R^(2b), R^(2c), andR^(2d) is independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a), or —OR^(a). Insome embodiments, T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d);wherein each R^(2a), R^(2b), R^(2c), and R^(2d) is independently H,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo,cyano, —CH₂OR^(a), or —OR^(a). In some embodiments, T is —CR^(2a)R^(2b)—or —CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein each R^(2a), R^(2b), R^(2c),and R^(2d) is independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₃₋₆halocycloalkyl, halo, or cyano. In some embodiments, T is—CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein each R^(2a),R^(2b), R^(2c), and R^(2d) is independently H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl or C₃₋₆halocycloalkyl. In some embodiments, T is—CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein each R^(2a),R^(2b), R^(2c), and R^(2d) is independently H, C₁₋₆alkyl, orC₃₋₆cycloalkyl.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d); whereinR^(2a), R^(2b), R^(2c), and R^(2d) are independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), —OR^(a) or —NHR^(a). In some embodiments, T is—CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b),R^(2c), and R^(2d) are independently H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),or —OR^(a). In some embodiments, T is —CR^(2a)R^(2b)— or—CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b), R^(2c), and R^(2d)are independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₃₋₆halocycloalkyl, or halo. In some embodiments, T is —CR^(2a)R^(2b)—or —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b), R^(2c), andR^(2d) are independently H or halo. In some embodiments, T is—CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein, R^(2a),R^(2b), R^(2c), and R^(2d) are independently H, —C(O)—NH(R^(a))—,—NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—, —S(O)_(n)—NH(R^(a))—,—S(O)_(n)R^(a)—, or —O—C(O)—NHR^(a). In some embodiments, T is—CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b),R^(2c), and R^(2d) are independently H, —OR^(a), —NHR^(a),—C(O)—NH(R^(a)), —NR^(e)—C(O)R^(a), or —NR^(e)—S(O)_(n)R^(a). In someembodiments, T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d)d,wherein R^(2a), R^(2b), R^(2c), and R^(2d) are independently H, —OR^(a),or —O—C(O)—NHR^(a). In some embodiments, T is —CR^(2a)R^(2b)— or—CR^(2a)R^(2b)CR^(2c)R^(2d), wherein R^(2a), R^(2b), R^(2c), and R^(2d)are independently H, —S(O)_(n)—NH(R^(a)), or —S(O)_(n)—R^(a)—. In someembodiments, T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d),wherein R^(2a), R^(2b), R^(2c), and R^(2d) are independently H, halo,cyano, —NHR^(a)— or —OR^(a). In some embodiments, T is —CR^(2a)R^(2b)—or —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b), R^(2c), andR^(2d) are independently H or —NHR^(a). In some embodiments, T is—CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b),R^(2c), and R^(2d) are independently is H, halo, cyano, or —OR^(a). Insome embodiments, T is —CR^(2a)R^(2b)— or —CR^(2a)R^(2b)—CR^(2c)R^(2d),wherein R^(2a), R^(2b), R^(2c), and R^(2d) are independently H or cyano.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— wherein, R^(2a) and R^(2b) together with thecarbon to which they are attached form a (i) 3 to 7 membered carbocyclicring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2heteroatoms selected from N, O, and S, wherein the 3 to 7 memberedcarbocyclic ring or the 4 to 7 membered heterocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁-C₆alkyl, C₃-C₆cycloloalkyl or—OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— wherein, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 3 to 7 membered carbocyclicring, wherein the 3 to 7 membered carbocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁-C₆alkyl, C₃-C₆cycloloalkyl or—OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— wherein, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 3 to 5 membered carbocyclicring, wherein the 3 to 5 membered carbocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁-C₆alkyl, C₃-C₆cycloloalkyl or—OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b) wherein, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 3 to 5 membered carbocyclicring, wherein the 3 to 5 membered carbocyclic ring.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— wherein, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 4 to 7 membered heterocyclicring containing 1 or 2 heteroatoms selected from N, O, and S, whereinthe 4 to 7 membered heterocyclic ring is optionally substituted with oneto three R^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁-C₆alkyl, C₃-C₆cycloloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— wherein, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 4 to 5 membered heterocyclicring containing 1 or 2 heteroatoms selected from N, O, and S, whereinthe 4 to 5 membered heterocyclic ring is optionally substituted with oneto three R^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁-C₆alkyl, C₃-C₆cycloloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)— wherein, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 4 to 5 membered heterocyclicring containing 1 or 2 heteroatoms selected from N, O, and S.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)—, wherein R^(2a) and R^(2b) are independentlyH, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo,cyano, —CH₂R^(a)—, —CH₂OR^(a), —OR^(a) or —NHR^(a). In some embodiments,T is —CR^(2a)R^(2b)—, wherein R^(2a) and R^(2b) are independently H,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo,cyano, —CH₂R^(a)—, —CH₂OR^(a), or —OR^(a). In some embodiments, T is—CR^(2a)R^(2b)—, wherein R^(2a) and R^(2b) are independently H,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, or halo.In some embodiments, T is —CR^(2a)R^(2b)—, wherein R^(2a) and R^(2b) areindependently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, or halo. In someembodiments, T is —CR^(2a)R^(2b)—, wherein R^(2a) and R^(2b) areindependently H or halo. In some embodiments, T is —CR^(2a)R^(2b)—,wherein, R^(2a) and R^(2b) are independently H, —C(O)—NH(R^(a))—,—NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—, —S(O)_(n)—NH(R^(a))—,—S(O)_(n)—R^(a)—, or —O—C(O)—NHR^(a). In some embodiments, T is—CR^(2a)R^(2b), wherein R^(2a) and R^(2b) are independently H, —OR^(a),—NHR^(a), —C(O)—NH(R^(a)), —NR^(e)—C(O)R^(a), or —NR^(e)—S(O)_(n)R^(a).In some embodiments, T is —CR^(2a)R^(2b)—, wherein R^(2a) and R^(2b) areindependently H, —OR^(a), or —O—C(O)—NHR^(a). In some embodiments, T is—CR^(2a)R^(2b), wherein R^(2a) and R^(2b) are independently H,—S(O)_(n)—NH(R^(a)), or —S(O)_(n)—R^(a)—. In some embodiments, T is—CR^(2a)R^(2b), wherein R^(2a) and R^(2b) are independently H, halo,cyano, —NHR^(a)— or —OR^(a). In some embodiments, T is —CR^(2a)R^(2b),wherein R^(2a) and R^(2b) are independently H or —NHR^(a). In someembodiments, T is —CR^(2a)R^(2b), wherein R^(2a) and R^(2b) areindependently is H, halo, cyano, or —OR^(a). In some embodiments, T is—CR^(2a)R^(2b)—, wherein R^(2a) and R^(2b) are independently H or cyano.In some embodiments, T is —CR^(2a)R^(2b)—, wherein R^(2a) and R^(2b) areeach H.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)—; wherein each R^(2a) and R^(2b) isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),—CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or R^(2a) and R^(2b) togetherwith the carbon atom to which they are attached form (i) a 3 to 7membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ringcontaining 1 or 2 heteroatoms selected from N, O, and S, wherein the 3to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ringis optionally substituted with one to three R^(A2), wherein each R^(A2)is independently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)—; wherein each R^(2a) and R^(2b) isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),—CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or R^(2a) and R^(2b) togetherwith the carbon atom to which they are attached form a 3 to 7 memberedcarbocyclic ring wherein the 3 to 7 membered carbocyclic ring isoptionally substituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)—; wherein each R^(2a) and R^(2b) isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),—CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)—R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or R^(2a) and R^(2b) togetherwith the carbon atom to which they are attached form a 3 to 5 memberedcarbocyclic ring, wherein the 3 to 5 membered carbocyclic ring isoptionally substituted with one to three R^(A1), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(2b)—; wherein each R^(2a) and R^(2b) isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),—CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or R^(2a) and R^(2b) togetherwith the carbon atom to which they are attached form a 3 memberedcarbocyclic ring, wherein the 3 membered carbocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T is —CR^(2a)R^(b); wherein each R^(2a) and R^(2b) is independentlyH, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo,cyano, —CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a),—O—C(O)—NHR^(a), —NR^(a)—, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—,—NR^(e)—S(O)_(n)R^(a)—, —S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; orR^(2a) and R^(2b) together with the carbon atom to which they areattached form a 3 membered carbocyclic ring.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T —CR^(2a)R^(2b), wherein R^(2a) and R^(2b) are independently H,halo, or —OR^(a). In some embodiments, T is —CR^(2a)R^(b)—, whereinR^(2a) and R^(2b) are independently H, halo, or —OR^(a), and each R^(a)is independently H or C₁₋₆alkyl. In some embodiments, T is—CR^(2a)R^(b), wherein R^(2a) and R^(2b) are independently H, halo, or—OR^(a), and each R^(a) is independently H or C₁₋₃ alkyl. In someembodiments, T is —CR^(2a)R^(b)—, wherein R^(2a) and R^(2b) areindependently H, halo, or —OR^(a), and each R^(a) is independently H ormethyl.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T —CR^(2a)R^(2b)—CR^(2c)R^(2d); wherein R^(2a), R^(2b), R^(2c), andR^(2d) are independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a), —OR^(a) or—NHR^(a). In some embodiments, T is —CR^(2a)R^(2b)—CR^(2c)R^(2d),wherein R^(2a), R^(2b), R^(2c), and R^(2d) are independently H,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo,cyano, —CH₂R^(a)—, —CH₂OR^(a), or —OR^(a). In some embodiments, T is—CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b), R^(2c), and R^(2d)are independently H, C₁₋₆-alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₃₋₆halocycloalkyl, or halo. In some embodiments, T is—CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b), R^(2c), and R^(2d)are independently H, C₁₋₆alkyl, C₃₋₆cycloalkyl or halo. In someembodiments, T is —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b),R^(2c), and R^(2d) are independently H or halo. In some embodiments, Tis —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein, R^(2a), R^(2b), R^(2c), andR^(2d) are independently H, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—,—NR^(e)—S(O)_(n)R^(a)—, —S(O)_(n)—NH(R^(a)), —S(O)_(n)—R^(a)—, or—O—C(O)—NHR^(a). In some embodiments, T is —CR^(2a)R^(2b)—CR^(2c)R^(2d),wherein R^(2a), R^(2b), R^(2c), and R^(2d) are independently H, —OR^(a),—NHR^(a), —C(O)—NH(R^(a)), —NR^(e)—C(O)R^(a), or —NR^(e)—S(O)_(n)R^(a).In some embodiments, T is —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a),R^(2b), R^(2c), and R^(2d) are independently H, —OR^(a), or—O—C(O)—NHR^(a). In some embodiments, T is —CR^(2a)R^(2b)CR^(2c)R^(2d),wherein R^(2a), R^(2b), R^(2c), and R^(2d) are independently H,—S(O)_(n)—NH(R^(a)), or —S(O)_(n)—R^(a)—; In some embodiments, T is—CR^(2a)R^(2b)CR^(2c)R^(2d), wherein R^(2a), R^(2b), R^(2c), and R^(2d)are independently H, halo, cyano, —NHR^(a)— or —OR^(a). In someembodiments, T is —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b),R^(2c), and R^(2d) are independently H or —NHR^(a). In some embodiments,T is —CR^(2a)R^(2b)CR^(2c)R^(2d), wherein R^(2a), R^(2b), R^(2c), andR^(2d) are independently is H, halo, cyano, or —OR^(a). In someembodiments, T is —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b),R^(2c), and R^(2d) are independently H or cyano. In some embodiments, Tis —CR^(2a)R^(2b)—CR^(2c)R^(2d), wherein R^(2a), R^(2b), R^(2c), andR^(2d) are each H.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, orIIb, T —CR^(2a)R^(2b)—CR^(2c)R^(2d)—; wherein R², R^(2b), R^(2c), andR^(2d) are independently H, halo, or —OR^(a). In some embodiments, T is—CR^(2a)R^(2b)CR^(2c)R^(2d)—, wherein R^(2a), R^(2b), R^(2c), and R^(2d)are independently H, halo, or —OR^(a), and each R^(a) is independently Hor C₁₋₆alkyl. In some embodiments, T is —CR^(2a)R^(2b)CR^(2c)R^(2d)—,wherein R^(2a), R^(2b), R^(2c), and R² are independently H, halo, or—OR^(a), and each R^(a) is independently H or C₁₋₃ alkyl. In someembodiments, T is —CR^(2a)R^(2b)—CR^(2c)R^(2d)—, wherein R^(2a), R^(2b),R^(2c), and R^(2d) are independently H, halo, or —OR^(a), and each R^(a)is independently H or methyl.

In some embodiments, the compound of Formula I or II is a compound ofFormula III:

In some embodiments, the compound of Formula I, Ia, II, or IIa is acompound of Formula IIIa:

In some embodiments, the compound of Formula I, Ib, II, or IIb is acompound of Formula IIIb:

In some embodiments of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, or IIIb, U is —NR¹¹—, —CR^(12a)R^(12b)—, —S—, —S(O)_(n)—,—S(O)₂—, —C(O)—, or —O—. In some embodiments, the compound of Formula I,Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, II is —NR¹¹, —CR^(12a)R^(12b),—C(O)— or —O—. In some embodiments, U is —NR¹¹, —CR^(12a)R^(12b), or—O—. In some embodiments, U is —NR¹¹ or —CR^(12a)R^(12b). In someembodiments, U is —NR¹¹.

In some embodiments of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, or IIIb, U is —O—, —C(O)—, —S—, —S(O)_(n)—, or —S(O)₂—. Insome embodiments, U is —O— or —C(O)—. In some embodiments, U is —S—,—S(O)_(n)—, or —S(O)₂—. In some embodiments, U is —S—. In someembodiments, U is —S(O)_(n)—. In some embodiments, U is —S(O)₂—. In someembodiments, U is —C(O)—. In some embodiments, U is —O—.

In some embodiments of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, or IIIb, R¹¹ is H, C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,C₃₋₆halocycloalkyl, —C(O)—R^(a), —S—R^(a), —S(O)—R^(a), —S(O)₂—R^(a),—CH₂—R^(a). In some embodiments, R¹¹ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₃-C₆cycloalkyl, or C₃-C₆halocycloalkyl. In some embodiments, R¹¹ is H,C₃-C₆cycloalkyl, or C₃-C₆halocycloalkyl. In some embodiments, R¹¹ is H,C₁-C₄ alkyl or C₁-C₄ haloalkyl. In some embodiments, R¹¹ is H or C₁-C₄alkyl. In some embodiments, R¹¹ is C₃-C₆halocycloalkyl. In someembodiments, R¹¹ is C₃-C₆cycloalkyl. In some embodiments, R¹¹ is C₁-C₄haloalkyl. In some embodiments, R¹¹ is C₁-C₄ alkyl. In some embodiments,R¹¹ is H. In some embodiments, R¹¹ is —C(O)—R^(a), —S—R^(a),—S(O)—R^(a), —S(O)₂—R^(a), —CH₂—R^(a).

In some embodiments, the compound of Formula I, II, or III has a FormulaIV:

In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa,or IV has a Formula IVa:

In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb,or IV has a Formula IVb:

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, R^(2a) and R^(2b) together with thecarbon to which they are attached form a (i) 3 to 7 membered carbocyclicring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2heteroatoms selected from N, O, and S, wherein the 3 to 7 memberedcarbocyclic ring or the 4 to 7 membered heterocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁-C₆alkyl, C₃-C₆cycloloalkyl or—OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 3 to 7 membered carbocyclicring, wherein the 3 to 7 membered carbocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁-C₆alkyl, C₃-C₆cycloloalkyl or—OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 3 to 5 membered carbocyclicring, wherein the 3 to 5 membered carbocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁-C₆alkyl, C₃-C₆cycloloalkyl or—OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 3 to 5 membered carbocyclicring, wherein the 3 to 5 membered carbocyclic ring.

In some embodiments, of the compound of Formula I, Ia, Ib, II Ha, IIb,III, IIIa, IIIb, IV, IVa, and IVb, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 4 to 7 membered heterocyclicring containing 1 or 2 heteroatoms selected from N, O, and S, whereinthe 4 to 7 membered heterocyclic ring is optionally substituted with oneto three R^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁-C₆alkyl, C₃-C₆cycloloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 3 to 5 membered heterocyclicring containing 1 or 2 heteroatoms selected from N, O, and S, whereinthe 3 to 5 membered heterocyclic ring is optionally substituted with oneto three R^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁-C₆alkyl, C₃-C₆cycloloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, R^(2a) and R^(2b) together with thecarbon to which they are attached form a 3 to 5 membered heterocyclicring containing 1 or 2 heteroatoms selected from N, O, and S.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, R^(2a) and R^(2b) are independentlyH, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo,cyano, —CH₂R^(a)—, —CH₂OR^(a), —OR^(a) or —NHR^(a). In some embodiments,T is —CR^(2a)R^(2b)—, wherein R^(2a) and R^(2b) are independently H,C₁₋₆-alkyl, C₃₄cycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a), or—OR^(a). In some embodiments, T is —CR^(2a)R^(2b)—, wherein R^(2a) andR^(2b) are independently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, or halo. In someembodiments, T is —CR^(2a)R^(2b)—, wherein R^(2a) and R^(2b) areindependently H or halo. In some embodiments, T is —CR^(2a)R^(2b)—,wherein, R^(2a) and R^(2b) are independently H, —C(O)—NH(R^(a))—,—NR^(e)—C(O)R^(a)—, —S(O)_(n)R^(a)—, —S(O)_(n)—NH(R^(a))—,—S(O)_(n)—R^(a)—, or —O—C(O)—NHR^(a). In some embodiments, T is—CR^(2a)R^(2b), wherein R^(2a) and R^(2b) are independently H, —OR^(a),—NHR^(a), —C(O)—NH(R^(a)), —NR^(e)—C(O)R^(a), or —NR^(e)—S(O)_(n)R^(a).In some embodiments, T is —CR^(2a)R^(2b)—, wherein R^(2a) and R^(2b) areindependently H, —OR^(a), or —O—C(O)—NHR^(a). In some embodiments, T is—CR^(2a)R^(2b), wherein R^(2′) and R^(b) are independently H,—S(O)_(n)—NH(R^(a)), or —S(O)_(n)—R^(a)—. In some embodiments, T is—CR^(2a)R^(2b), wherein R^(2a) and R^(2b) are independently H, halo,cyano, —NHR^(a)— or —OR^(a). In some embodiments, T is —CR^(2a)R^(2b),wherein R^(2a) and R^(2b) are independently H or —NHR^(a). In someembodiments, T is —CR^(2a)R^(2b), wherein R^(2a) and R^(2b) areindependently is H, halo, cyano, or —OR^(a). In some embodiments, T is—CR^(2a)R^(2b), wherein R^(2a) and R^(2b) are independently H or cyano.In some embodiments, T is —CR^(2a)R^(2b), wherein R^(2a) and R^(2b) areeach H.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, each R^(2a) and R^(2b) isindependently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—,—CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NHR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)R^(a)—; or R^(2a) and R^(2b) togetherwith the carbon atom to which they are attached form (i) a 3 to 7membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ringcontaining 1 or 2 heteroatoms selected from N, O, and S, wherein the 3to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ringis optionally substituted with one to three R^(A2), wherein each R^(A2)is independently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(a).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, each R^(2a) and R^(2b) isindependently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—,—CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NR^(a)—,—C(O)—NH(R^(a))—, —NR^(a)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or R^(2a) and R^(2b) togetherwith the carbon atom to which they are attached form a 3 to 7 memberedcarbocyclic ring wherein the 3 to 7 membered carbocyclic ring isoptionally substituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, each R^(2a) and R^(2b) isindependently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—,—CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or R^(2a) and R^(2b) togetherwith the carbon atom to which they are attached form a 3 to 5 memberedcarbocyclic ring, wherein the 3 to 5 membered carbocyclic ring isoptionally substituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, each R^(2a) and R^(2b) isindependently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—,—CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or R^(2a) and R^(2b) togetherwith the carbon atom to which they are attached form a 3 memberedcarbocyclic ring, wherein the 3 membered carbocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, each R^(2a) and R^(2b) isindependently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—,—CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a)—, —NR^(a)—,—C(O)—NH(R^(a))—, —NR^(a)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or R^(2a) and R^(2b) togetherwith the carbon atom to which they are attached form a 3 memberedcarbocyclic ring.

In some embodiments for the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, R^(12a) and R^(12b) are independentlyH, —OR^(a), or —O—C(O)—NHR^(a). In some embodiments, R^(12a) and R^(12b)are independently H, —NHR^(a), —C(O)—NH(R^(a)), —NR^(e)—C(O)R^(a),—NR^(e)—S(O)_(n)R^(a). In some embodiments, R^(12a) and R^(12b) areindependently H, —S(O)_(n)—NH(R^(a)), or —S(O)_(n)—R^(a)—. In someembodiments, R^(12a) and R^(12b) are independently H, halo, cyano,—NHR^(a)— or —OR^(a). In some embodiments, R^(12a) and R^(12b) areindependently H or —NHR^(a). In some embodiments, R^(12a) and R^(12b)are independently H, halo, cyano, or —OR^(a). In some embodiments,R^(12a) and R^(12b) are independently H or cyano. In some embodiments,R^(12a) and R^(12b) are independently H or —OR^(a). In some embodiments,R^(12a) and R^(12b) are independently H or —OR^(a), and R^(a) isC₃₋₆cycloalkyl. In some embodiments, R^(12a) and R^(12b) areindependently H or —OR^(a), and R^(a) is C₁₋₄ haloalkyl. In someembodiments, R^(12a) and R^(12b) are independently H or —OR^(a), andR^(a) is C₁₋₆alkyl optionally substituted with —O—C₁₋₄alkyl.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIa, IIIb, IV, IVa, or IVb, R^(12a) and R^(12b) together withthe carbon atom to which they are attached form a (i) 3 to 7 memberedcarbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 memberedcarbocyclic ring or the 4 to 7 membered heterocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₁₋₆cycloloalkyl or —OR^(e).

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, or IVb, R^(12a) and R^(12b) together withthe carbon atom to which they are attached form a 3 to 7 memberedcarbocyclic ring, wherein the 3 to 7 membered carbocyclic ring isoptionally substituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₁₋₆cycloloalkyl or —OR^(e).

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, or IVb, R^(12a) and R^(12b) together withthe carbon atom to which they are attached form a 4 to 7 memberedheterocyclic ring containing 1 or 2 heteroatoms selected from N, O, andS, wherein the 4 to 7 membered heterocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₁₋₆cycloloalkyl or —OR^(e).

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, or IVb, R^(12a) and R^(12b) together withthe carbon atom to which they are attached form a (i) 3 to 7 memberedcarbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 memberedcarbocyclic ring or the 4 to 7 membered heterocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₁₋₆cycloloalkyl.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, or IVb, R^(12a) and R^(12b) together withthe carbon atom to which they are attached form a (i) 3 to 7 memberedcarbocyclic ring or (ii) 3 to 5 membered heterocyclic ring containing 1or 2 heteroatoms selected from N, O, and S, wherein the 3 to 5 memberedcarbocyclic ring or the 3 to 5 membered heterocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₁₋₆cycloloalkyl.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, or IVb, R^(12a) and R^(12b) together withthe carbon atom to which they are attached form a (i) 3 to 7 memberedcarbocyclic ring or (ii) 3 to 5 membered heterocyclic ring containing 1or 2 heteroatoms selected from N, O, and S.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, or IVb, R^(12a) and R^(12b) together withthe carbon atom to which they are attached form a 3 to 5 memberedcarbocyclic ring, wherein the 3 to 5 membered carbocyclic ring isoptionally substituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₁₋₆cycloloalkyl.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, or IVb, R^(12a) and R^(12b) together withthe carbon atom to which they are attached form a 3 to 5 memberedheterocyclic ring containing 1 or 2 heteroatoms selected from N, O, andS, wherein the 3 to 5 membered heterocyclic ring is optionallysubstituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₁₋₆cycloloalkyl.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, or IVb, R^(12a) and R^(12b) together withthe carbon atom to which they are attached form a 3 to 5 memberedcarbocyclic ring.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, or IVb, R^(12a) and R^(12b) together withthe carbon atom to which they are attached form a 3 to 5 memberedheterocyclic ring containing 1 or 2 heteroatoms selected from N, O, andS.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, or IVb, R^(12a) and R^(12b) together withthe carbon atom to which they are attached form a 3 membered carbocyclicring.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, or IVb, each R^(2a), R^(2b), R^(12a), andR^(12b) is independently H, halo, or —OR^(a). In some embodiments, eachR^(2a), R^(2b), R^(12a), and R^(12b) is independently H, halo, or—OR^(a) and each R^(a) is independently H or C₁₋₆alkyl. In someembodiments, each R^(2a), R^(2b), R^(12a), and R^(12b) is independentlyH, halo, or —OR^(a) and each R^(a) is independently H or C₁₋₃ alkyl. Insome embodiments, each R^(2a), R^(2b), R^(12a), and R^(12b) isindependently H, halo, or —OR^(a) and each R^(a) is independently H ormethyl.

In some embodiments, the compound of Formula I or II has a Formula V:

In some embodiments, the compound of Formula I, Ia, II, or IIa has aFormula Va:

In some embodiments, the compound of Formula I, Ib, II, or IIb has aFormula Vb:

In some embodiments, of the compound of Formula V, Va, and Vb, R^(2a)and R^(12a) are independently H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),—OR^(a) or —NHR^(a). In some embodiments, R^(2a) and R^(12a) areindependently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—,—CH₂OR^(a), or —OR^(a). In some embodiments, R^(2a) and R^(12a) areindependently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, or halo. In someembodiments, R^(2a) and R^(12a) are independently H or halo. In someembodiments, R^(2a) and R^(12a) are independently H, —C(O)—NH(R^(a))—,—NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—, —S(O)_(n)—NH(R^(a))—,—S(O)_(n)—R^(a)—, or —O—C(O)—NHR^(a). In some embodiments, R^(2a) andR^(12a) are independently H, —OR^(a), —NHR^(a), —C(O)—NH(R^(a)),—NR^(e)—C(O)R^(a), or —NR^(e)—S(O)_(n)R^(a). In some embodiments, R^(2a)and R^(12a) are independently H, —OR^(a), or —O—C(O)—NHR^(a). In someembodiments, R^(2a) and R^(12a) are independently H,—S(O)_(n)—NH(R^(a)), or —S(O)_(n)—R^(a)—; In some embodiments, R^(2a)and R^(12a) are independently H, halo, cyano, —NHR^(a)— or —OR^(a). Insome embodiments, R^(2a) and R^(12a) are independently H or —NHR^(a). Insome embodiments, R^(2a) and R^(12a) are independently is H, halo,cyano, or —OR^(a). In some embodiments, R^(2a) and R^(12a) areindependently H or cyano. In some embodiments, R^(2a) and R^(12a) areeach H.

In some embodiments, of the compound of Formula V, Va, and Vb, R^(2a)and R^(12a) are independently H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a)—, —NHR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a).

In some embodiments, of the compound of Formula V, Va, and Vb, R^(2a)and R^(12a) are independently H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl, C₃₋₆halocycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a)—, —NHR^(a),C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—.

In some embodiments, of the compound of Formula V, Va, and Vb, R^(2a)and R^(12a) are independently H, C₁₋₆alkyl, C₃₄cycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a), —OR^(a), —O—C(O)—NHR^(a),—NHR^(a)—, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—;

In some embodiments, of the compound of Formula V, Va, and Vb, R^(2a)and R^(12a) are independently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a), —OR^(a), —O—C(O)—NHR^(a),—NHR^(a)—, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—;

In some embodiments, of the compound of Formula V, Va, and Vb, R^(2a)and R^(12a) are independently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a), —OR^(a), —O—C(O)—NHR^(a),—NHR^(a)—, —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—;

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W¹ is a bond or—CR^(4a)R^(4b)—R^(4a); wherein R^(4b) and R^(4b) are independently H,C₁₋₆alkyl, C₁₋₄haloalkyl, halo, hydroxyl, cyano, —O—C₁₋₄alkyl, orC₁₋₄alkylene-O—C₁₋₄alkyl; or R^(4a) and R^(4b) together with the carbonatom to which they are attached form (i) a 3 to 7 membered carbocyclicring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2heteroatoms selected from N, O, and S, wherein the 3 to 7 memberedcarbocyclic ring or the 4 to 7 membered heterocyclic ring is optionallysubstituted with one to three R^(A3), wherein each R^(A3) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e). Insome embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W¹ is a bond or—CR^(4a)R^(4b)—R^(4a), wherein R^(4a) and R^(4b) are independently H,C₁₋₆alkyl, C₁₋₄haloalkyl, halo, hydroxyl, cyano, —O—C₁₋₄alkyl, orC₁₋₆alkylene-O—C₁₋₄alkyl. In some embodiments, W¹ is a bond or—CR^(4a)R^(4b)—R^(4a), wherein R^(4a) and R^(4b) are independently H,C₁₋₆ alkyl, halo, C₁₋₄haloalkyl, or cyano. In some embodiments, W¹ is abond or —CR^(4a)R^(4b)—R^(4a), wherein R^(4a) and R^(4b) areindependently H, C₁-C₆ alkyl, halo, or cyano. In some embodiments, W¹ isa bond or —CR^(4a)R^(4b)—R^(4a), wherein R^(4a) and R^(4b) areindependently H, halo, or C₁-C₄ alkyl. In some embodiments, W¹ is a bondor —CR^(4a)R^(4b)—R^(4a), wherein R^(4a) and R^(4b) are independently H,fluoro, chloro, or C₁-C₄ alkyl. In some embodiments, W¹ is a bond or—CR^(4a)R^(4b)—R^(4a), wherein R^(4a) and R^(4b) are independently H orcyano. In some embodiments, W¹ is a bond or —CR^(4a)R^(4b)—R^(4a),wherein R^(4a) and R^(4b) are independently H or C₁₋₄haloalkyl.

In some embodiments, W¹ is a bond or —CR^(4a)R^(4b)—, wherein R^(4a) andR^(4b) together with the carbon atom to which they are attached form (i)a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 memberedheterocyclic ring containing 0 to 2 heteroatoms selected from N, O, andS, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 memberedheterocyclic ring is optionally substituted with one to three R^(A3),wherein each R^(A3) is independently oxo, halo, cyano, C₁₋₆alkyl,C₃₋₆cycloalkyl or —OR^(e). In some embodiments, W¹ is a bond or—CR^(4b)—, wherein R^(4a) and R^(4b) together with the carbon atom towhich they are attached form (i) a 3 to 7 membered carbocyclic ring or(ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatomsselected from N, O, and S, wherein the 3 to 7 membered carbocyclic ringor the 4 to 7 membered heterocyclic ring is optionally substituted withone to three R^(A3), wherein each R^(A3) is independently oxo, halo,cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In some embodiments, W¹ is a bondor —CR⁴% R^(b)—R^(4a), wherein R^(4a) and R^(4b) together with thecarbon atom to which they are attached form a 3 to 7 memberedcarbocyclic ring, wherein the 3 to 7 membered carbocyclic ring isoptionally substituted with one to three R^(A3), wherein each R^(A3) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In someembodiments, W¹ is a bond or —CR⁴% R^(b)—, wherein R^(4a) and R^(4b)together with the carbon atom to which they are attached form a 4 to 7membered heterocyclic ring containing 1 or 2 heteroatoms selected fromN, O, and S, wherein the 4 to 7 membered heterocyclic ring is optionallysubstituted with one to three R^(A3), wherein each R^(A3) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In someembodiments, W¹ is a bond or —CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b)together with the carbon atom to which they are attached form (i) a 3 to7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ringcontaining 1 or 2 heteroatoms selected from N, O, and S. In someembodiments, W¹ is a bond or —CR⁴% R^(b)—, wherein R^(4a) and R^(4b)together with the carbon atom to which they are attached form a 3 to 7membered carbocyclic ring.

In some embodiments, W¹ is a bond or —CR⁴% R^(b)—, wherein R^(4a) andR^(4b) together with the carbon atom to which they are attached form a 3membered carbocyclic ring optionally substituted with one to threeR^(A3), wherein each R^(A3) is independently oxo, halo, cyano,C₁₋₆alkyl, or C₃₋₆cycloalkyl.

In some embodiments of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W¹ is —CR^(4a)R^(4b)—,wherein R^(4b) and R^(4b) are independently H, C₁₋₆alkyl, C₁₋₄haloalkyl,halo, hydroxyl, cyano, —O—C₁₋₄alkyl, or C₁₋₄alkylene-O—C₁₋₄-alkyl; orR^(4a) and R^(4b) together with the carbon atom to which they areattached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7membered heterocyclic ring containing 1 or 2 heteroatoms selected fromN, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7membered heterocyclic ring is optionally substituted with one to threeR^(A3), wherein each R^(A3) is independently oxo, halo, cyano,C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e). In some embodiments of thecompound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa,IVb, V, Va, or Vb, W¹ is —CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b) areindependently H, C₁₋₆alkyl, C₁₋₄haloalkyl, halo, hydroxyl, cyano,—O—C₁₋₄alkyl, or C₁₋₄alkylene-O—C₁₋₆alkyl. In some embodiments W¹is-CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b) are independently H, C₁-C₆alkyl, halo, C₁₋₄haloalkyl, or cyano. In some embodiments, W¹ is—CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b) are independently H, C₁-C₆alkyl, halo, or cyano. In some embodiments, W¹ is a bond or—CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b) are independently H, halo, orC₁-C₄alkyl. In some embodiments, W¹ is a bond or —CR^(4a)R^(4b)—,wherein R^(4a) and R^(4b) are independently H, fluoro, chloro, or C₁-C₄alkyl. In some embodiments, W¹ is a bond or —CR^(4a)R^(4b)—, whereinR^(4a) and R^(4b) are independently H or cyano. In some embodiments, W¹is a bond or —CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b) areindependently H or C₁₋₆haloalkyl.

In some embodiments, W¹ is —CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b)together with the carbon atom to which they are attached form (i) a 3 to7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ringcontaining 1 or 2 heteroatoms selected from N, O, and S, wherein the 3to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ringis optionally substituted with one to three R^(A3), wherein each R^(A3)is independently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).In some embodiments, W¹ is-CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b)together with the carbon atom to which they are attached form (i) a 3 to7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ringcontaining 1 or 2 heteroatoms selected from N, O, and S, wherein the 3to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ringis optionally substituted with one to three R^(A3), wherein each R^(A3)is independently oxo, halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In someembodiments, W¹ is —CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b) togetherwith the carbon atom to which they are attached form a 3 to 7 memberedcarbocyclic ring, wherein the 3 to 7 membered carbocyclic ring isoptionally substituted with one to three R^(A3), wherein each R^(A3) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In someembodiments, W¹ is —CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b) togetherwith the carbon atom to which they are attached form a 4 to 7 memberedheterocyclic ring containing 1 or 2 heteroatoms selected from N, O, andS, wherein the 4 to 7 membered heterocyclic ring is optionallysubstituted with one to three R^(A3), wherein each R^(A3) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In someembodiments, W¹ is —CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b) togetherwith the carbon atom to which they are attached form (i) a 3 to 7membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ringcontaining 1 or 2 heteroatoms selected from N, O, and S. In someembodiments, W¹ is a bond or —CR^(4a)R^(4b)—, wherein R^(4a) and R^(4b)together with the carbon atom to which they are attached form a 3 to 7membered carbocyclic ring. In some embodiments, W¹ is —CR^(4a)R^(4b)—,wherein R^(4a) and R^(4b) together with the carbon atom to which theyare attached form a 3 membered carbocyclic ring optionally substitutedwith one to three R^(A3), wherein each R^(A3) is independently oxo,halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W¹ is a bond.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W² is —CR^(5a)R^(5b)—.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W² is —CR^(6a)═CR^(6b)—,wherein R^(6a) and R^(6b) is independently H, halo, C₁₋₄haloalkyl, orC₁₋₆alkyl. In some embodiments, W² is —CR^(6a)═CR^(6b)—, wherein eachR^(6a) and R^(6b) together with the carbon atoms to which each isattached form (i) a 5 to 10 membered carbocyclic ring, (ii) 5 to 10membered heterocyclic ring containing 1 or 2 heteroatom selected from N,O, and S, (iii) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10membered heteroaromatic ring containing 1 to 3 heteroatoms selected fromN, O and S, wherein the 5 to 10 membered carbocyclic ring, 5 to 10membered heterocyclic ring, 6 to 10 membered aromatic ring, or 5 to 10membered heteroaromatic ring is optionally substituted with one to fourR^(A4), wherein each R^(A4) is independently halo or C₁₋₆alkyl.

In some embodiments, W² is —CR^(6a)═CR^(6b)—, wherein each R^(6a) andR^(6b) together with the carbon atoms to which each is attached form (i)a 6 to 10 membered aromatic ring, or (ii) a 5 to 10 memberedheteroaromatic ring containing 1 to 3 heteroatoms selected from N, O andS, wherein the 6 to 10 membered aromatic ring or the 5 to 10 memberedheteroaromatic ring is optionally substituted with one to four R^(A4),wherein each R^(A4) is independently halo or C₁₋₆alkyl.

In some embodiments, W² is —CR^(6a)═CR^(6b)—, wherein each R^(6a) andR^(6b) together with the carbon atoms to which each is attached form (i)a 5 to 10 membered carbocyclic ring or (ii) a 5 to 10 memberedheterocyclic ring containing 1 or 2 heteroatom selected from N, O, andS, wherein the 5 to 10 membered carbocyclic ring or the 5 to 10 memberedheterocyclic ring, is optionally substituted with one to four R^(A4),wherein each R^(A4) is independently halo or C₁₋₄alkyl.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, X is a bond. In someembodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III,IIIa, IIIb, IV, IVa, or IVb, X is —CR^(8a)R^(8b)—.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, Z is —CR^(9a)R^(9b)—.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, Z is —CR^(10a)═R^(10b)—,wherein each R^(10a) and R^(10b) is independently H, halo,C₁₋₄haloalkyl, or C₁₋₆alkyl. In some embodiments, Z is—CR^(10a)═CR^(10b)—, wherein each R^(10a) and R^(10b) together with thecarbon atoms to which each is attached form (i) a 5 to 10 memberedcarbocyclic ring, (ii) 5 to 10 membered heterocyclic ring containing 1or 2 heteroatom selected from N, O, and S, (iii) a 6 to 10 memberedaromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing1 to 3 heteroatoms selected from N, O and S, wherein the 5 to 10membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10membered aromatic ring, or 5 to 10 membered heteroaromatic ring isoptionally substituted with one to four R^(A4), wherein each R^(A4) isindependently halo, oxo, cyano, or C₁₋₆alkyl. In some embodiments, Z is—CR^(10a)═CR^(10b)—, wherein each R^(10a) and R^(10b) together with thecarbon atoms to which each is attached form (i) a 6 to 10 memberedaromatic ring, or (ii) a 5 to 10 membered heteroaromatic ring containing1 to 3 heteroatoms selected from N, O and S, wherein the 6 to 10membered aromatic ring or the 5 to 10 membered heteroaromatic ring isoptionally substituted with one to four R^(A4), wherein each R^(A4) isindependently halo or C₁₋₆alkyl. In some embodiments, Z is—CR^(10a)═CR^(10b)—, wherein each R^(10a) and R^(10b) together with thecarbon atoms to which each is attached form (i) a 5 to 10 memberedcarbocyclic ring or (ii) a 5 to 10 membered heterocyclic ring containing1 or 2 heteroatom selected from N, O, and S, wherein the 5 to 10membered carbocyclic ring or the 5 to 10 membered heterocyclic ring, isoptionally substituted with one to four R^(A4), wherein each R^(A4) isindependently halo or C₁₋₄alkyl.

In some embodiments, the compound of Formula I, IL, III, or IV has aFormula VI:

-   -   wherein m is 0, 1, 2, 3, or 4; and    -   each R² is independently C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano,        —CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a),        —O—C(O)—NHR^(a), —NHR^(a)—, —C(O)—NH(R^(a))—,        —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,        —S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or    -   two R² on same carbon atom, together with the carbon atom to        which they both are attached form a (i) 3 to 7 membered        carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring        containing 1 or 2 heteroatoms selected from N, O, and S, wherein        the 3 to 7 membered carbocyclic ring or the 4 to 7 membered        heterocyclic ring is optionally substituted with one to three        R^(A2), wherein each R^(A2) is independently oxo, halo, cyano,        C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa,IV, or IVa has a Formula VIa:

-   -   wherein m is 0, 1, 2, 3, or 4; and    -   each R² is independently C₁₋₆alkyl, or C₃₋₆cycloalkyl, halo,        cyano, —CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a),        —O—C(O)—NHR^(a), —NHR^(a)—, —C(O)—NH(R^(a))—,        —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,        —S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—;    -   or two R² on same carbon atom, together with the carbon atom to        which they both are attached form a (i) 3 to 7 membered        carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring        containing 1 or 2 heteroatoms selected from N, O, and S, wherein        the 3 to 7 membered carbocyclic ring or the 4 to 7 membered        heterocyclic ring is optionally substituted with one to three        R^(A2), wherein each R^(A2) is independently oxo, halo, cyano,        C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb,IV, or IVb has a Formula VIb:

-   -   wherein m is 0, 1, 2, 3, or 4; and    -   each R² is independently C₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano,        —CH₂R^(a)—, —CH₂OR^(a), —CH₂—S(O)_(n)R^(a)—, —OR^(a),        —O—C(O)—NHR^(a), —NHR^(a)—, —C(O)—NH(R^(a))—,        —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,        —S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a); or    -   two R² on same carbon atom, together with the carbon atom to        which they both are attached form a (i) 3 to 7 membered        carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring        containing 1 or 2 heteroatoms selected from N, O, and S, wherein        the 3 to 7 membered carbocyclic ring or the 4 to 7 membered        heterocyclic ring is optionally substituted with one to three        R^(A2), wherein each R^(A2) is independently oxo, halo, cyano,        C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is—CR^(3a)R^(3b)—, —C(O)—, —SO₂—, —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, or—N(R^(a))—. In some embodiments, L is —CR^(3a)R^(3b)—, —C(O)—,—CR^(3a)R^(3b)—CR^(3c)R^(3d)—, or —SO₂. In some embodiments, L is—CR^(3a)R^(3b)—, —C(O)— or —CR^(3a)R^(3b)—CR^(3c)R^(3d)—. In someembodiments, L is —CR^(3a)R^(3b)— or —CR^(3a)R^(3b)—CR^(3c)R^(3d)—. Insome embodiments, L is —C(O)—. In some embodiments, L is —SO₂—. In someembodiments, L is —CR^(3a)R^(3b)—CR^(3c)R^(3d)—. In some embodiments, Lis —N(R^(a))—. In some embodiments, L is —CR^(3a)R^(3b)—.

In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, R^(3a),R^(3b), R^(3c), and R^(3d) are independently H, C₁₋₆alkyl,C₁₋₄haloalkyl, or —O—C₁₋₄alkyl; or any one of (i) R^(3a) and R^(3b) or(ii) R^(3c) and R^(3d) together with the carbon atom to which they areattached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7membered heterocyclic ring containing 1 or 2 heteroatoms selected fromN, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7membered heterocyclic ring is optionally substituted with one to threeR^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e). In some embodiments, R^(3a),R^(3b), R^(3c), and R^(3d) are independently H, C₁₋₆alkyl,C₁₋₄haloalkyl, or —O—C₁₋₄alkyl; or any one of (i) R^(3a) and R^(3b) or(ii) R^(3c) and R^(3d) together with the carbon atom to which they areattached form a (i) 3 to 7 membered carbocyclic ring or (ii) 3 to 7membered heterocyclic ring containing 1 or 2 heteroatoms selected fromN, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7membered heterocyclic ring is optionally substituted with one or twoR^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁₋₆alkyl, or C₃₋₆cycloalkyl. In some embodiments, R^(3a), R^(3b),R^(3c), and R^(3d) are independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, or—O—C₁₋₄alkyl; or any one of (i) R^(3a) and R^(3b) or (ii) R^(3c) andR^(3d) together with the carbon atom to which they are attached form a 3membered carbocyclic ring, wherein the 3 membered carbocyclic ring isoptionally substituted with one or two R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In someembodiments, R^(3a), R^(3b), R^(3c), and R^(3d) are independently H,C₁₋₆alkyl, C₁₋₆haloalkyl, or —O—C₁₋₄alkyl; or any one of (i) R^(3a) andR^(3b) or (ii) R^(3c) and R^(3d) together with the carbon atom to whichthey are attached form a 3 membered carbocyclic ring. In someembodiments, R^(3a), R^(3b), R^(3c), and R^(3d) are independently H,C₁₋₆alkyl, C₁₋₄haloalkyl, or —O—C₁₋₄alkyl. In some embodiments, R^(3a),R^(3b), R^(3c), and R^(3d) are independently H, C₁₋₃alkyl,C₁₋₆haloalkyl, or —O—C₁₋₃alkyl. In some embodiments, R^(3a), R^(3b),R^(3c), and R^(3d) are independently H or C₁₋₃alkyl. In someembodiments, R^(3a), R^(3b), R^(3c), and R^(4d) are each H.

In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb,III, Ia, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is—CR^(3a)R^(3b)— or —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a),R^(3b), R^(3c), and R^(3d) are independently H, C₁₋₆alkyl,C₁₋₄haloalkyl, or —O—C₁₋₄alkyl; or any one of (i) R^(3a) and R^(3b) or(ii) R^(3c) and R^(3d) together with the carbon atom to which they areattached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7membered heterocyclic ring containing 1 or 2 heteroatoms selected fromN, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7membered heterocyclic ring is optionally substituted with one to threeR^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e). In some embodiments, L is—CR^(3a)R^(3b)— or —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R³⁸, R^(3b),R^(3c), and R^(3d) are independently H, C₁₋₆alkyl, C₁₋₄haloalkyl, or—O—C₁₋₄alkyl; or any one of (i) R^(3a) and R^(3b) or (ii) R^(3c) andR^(3d) together with the carbon atom to which they are attached form a(i) 3 to 7 membered carbocyclic ring or (ii) 3 to 7 memberedheterocyclic ring containing 1 or 2 heteroatoms selected from N, O, andS, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 memberedheterocyclic ring is optionally substituted with one or two R^(A2),wherein each R^(A2) is independently oxo, halo, cyano, C₁₋₆alkyl, orC₃₋₆cycloalkyl. In some embodiments, L is —CR^(3a)R^(3b)— or—CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a), R^(3b), R^(3c), andR^(3d) are independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, or —O—C₁₋₄alkyl;or any one of (i) R^(3a) and R^(3b) or (ii) R^(3c) and R^(3d) togetherwith the carbon atom to which they are attached form a 3 memberedcarbocyclic ring, wherein the 3 membered carbocyclic ring is optionallysubstituted with one or two R^(A2), wherein each R^(A2) is independentlyoxo, halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In some embodiments, Lis —CR^(3a)R^(3b)— or —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a),R^(3b), R^(3c), and R^(3d) are independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, or —O—C₁₋₄alkyl; or any one of (i) R^(3a) and R^(3b) or(ii) R^(3c) and R^(3d) together with the carbon atom to which they areattached form a 3 membered carbocyclic ring. In some embodiments, L is—CR^(3a)R^(3b)— or —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a),R^(3b), R^(3c), and R^(3d) are independently H, C₁₋₆alkyl,C₁₋₄haloalkyl, or —O—C₁₋₄alkyl. In some embodiments, R^(3a), R^(3b),R^(3c), and R^(3d) are independently H, C₁₋₃alkyl, C₁₋₃haloalkyl, or—O—C₁₋₃alkyl. In some embodiments, L is —CR^(3a)R^(3b)— or—CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a), R^(3b), R^(3c), andR^(3d) are independently H or C₁₋₃alkyl. In some embodiments, R^(3a),R^(3b), R^(3c), and R^(3d) are each H.

In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is—CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a), R^(3b), R^(3c), andR^(3d) are independently H, C₁₋₆alkyl, C₁₋₄haloalkyl, or —O—C₁₋₄alkyl;or any one of (i) R^(3a) and R^(3b) or (ii) R^(3c) and R^(3d) togetherwith the carbon atom to which they are attached form (i) a 3 to 7membered carbocyclic ring or (ii) a 3 to 7 membered heterocyclic ringcontaining 1 or 2 heteroatoms selected from N, O, and S, wherein the 3to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ringis optionally substituted with one to three R^(A2), wherein each R^(A2)is independently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).In some embodiments, L is —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a),R^(3b), R^(3c), and R^(3d) are independently H, C₁₋₆alkyl,C₁₋₄haloalkyl, or —O—C₁₋₄alkyl; or any one of (i) R^(3a) and R^(3b) or(ii) R^(3c) and R^(3d) together with the carbon atom to which they areattached form a (i) 3 to 7 membered carbocyclic ring or (ii) 3 to 7membered heterocyclic ring containing 1 or 2 heteroatoms selected fromN, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7membered heterocyclic ring is optionally substituted with one or twoR^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁₋₆alkyl, or C₃₋₆cycloalkyl. In some embodiments, L is—CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a), R^(3b), R^(3c), andR^(3d) are independently H, C₁₋₆alkyl, C₁₋₄haloalkyl, or —O—C₁₋₆alkyl;or any one of (i) R^(3a) and R^(3b) or (ii) R^(3c) and R^(3d) togetherwith the carbon atom to which they are attached form a 3 memberedcarbocyclic ring, wherein the 3 membered carbocyclic ring is optionallysubstituted with one or two R^(A2), wherein each R^(A2) is independentlyoxo, halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In some embodiments, Lis —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a), R^(3b), R^(3c), andR^(3d) are independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, or —O—C₁₋₆alkyl;or any one of (i) R^(3a) and R^(3b) or (ii) R^(3c) and R^(3d) togetherwith the carbon atom to which they are attached form a 3 memberedcarbocyclic ring. In some embodiments, L is—CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a), R^(3b), R^(3c), andR^(3d) are independently H, C₁₋₆alkyl, C₁₋₄haloalkyl, or —O—C₁₋₆alkyl.In some embodiments, R^(3a), R^(3b), R^(3c), and R^(3d) areindependently H, C₁₋₃alkyl, C₁₋₃haloalkyl, or —O—C₁₋₃alkyl. In someembodiments, L is —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a), R^(3b),R^(3c), and R^(3d) are independently H or C₁₋₃alkyl. In someembodiments, L is —CR^(3a)R^(3b)—CR^(3c)R^(3d)—, wherein R^(3a), R^(3b),R^(3c), and R^(3d) are each H.

In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb,III, Ia, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is—CR^(3a)R^(3b)—, wherein R^(3a) and R^(3b) are independently H,C₁₋₆alkyl, C₁₋₄haloalkyl, or —O—C₁₋₆alkyl; or any one of (i) R^(3a) andR^(3b) or (ii) R^(3c) and R^(3d) together with the carbon atom to whichthey are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selectedfrom N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3to 7 membered heterocyclic ring is optionally substituted with one tothree R^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e). In some embodiments, L is—CR^(3a)R^(3b)—, wherein R^(3a) and R^(3b) are independently H,C₁₋₆alkyl, C₁₋₄haloalkyl, or —O—C₁₋₆alkyl; or any one of (i) R^(3a) andR^(3b) or (ii) R³ and R^(3d) together with the carbon atom to which theyare attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 3 to 7membered heterocyclic ring containing 1 or 2 heteroatoms selected fromN, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7membered heterocyclic ring is optionally substituted with one or twoR^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁₋₆alkyl, or C₃₋₆cycloalkyl. In some embodiments, L is —CR^(3a)R^(3b)—,wherein R^(3a) and R^(3b) are independently H, C₁₋₆alkyl, C₁₋₄haloalkyl,or —O—C₁₋₄alkyl; or any one of (i) R^(3a) and R^(3b) or (ii) R^(3c) andR^(3d) together with the carbon atom to which they are attached form a 3membered carbocyclic ring, wherein the 3 membered carbocyclic ring isoptionally substituted with one or two R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In someembodiments, L is —CR^(3a)R^(3b)—, wherein R^(3a) and R^(3b) areindependently H, C₁₋₆alkyl, C₁₋₄haloalkyl, or —O—C₁₋₄alkyl; or any oneof (i) R^(3a) and R^(3b) or (ii) R^(3c) and R^(3d) together with thecarbon atom to which they are attached form a 3 membered carbocyclicring. In some embodiments, L is —CR^(3a)R^(3b)—, wherein R^(3a) andR^(3b) are independently H, C₁₋₆alkyl, C₁₋₄haloalkyl, or —O—C₁₋₄alkyl.In some embodiments, L is —CR^(3a)R^(3b)—, wherein R^(3a) and R^(3b) areindependently H, C₁₋₃alkyl, C₁₋₃haloalkyl, or —O—C₁₋₃alkyl. In someembodiments, L is —CR^(3a)R^(3b)—, wherein R^(3a) and R^(3b) areindependently H or C₁₋₃alkyl. In some embodiments, L is —CR^(3a)R^(3b)—,wherein R^(3a) and R^(3b) are each H.

In some embodiments, the compound of Formula I, IL, III, IV, or VI, hasa Formula VII:

In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa,IV, IVa, VI, or VIa, has a Formula VIIa:

In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb,IV, IVb, VI, or VIb, has a Formula VIIb:

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, andVIIb, R¹ is a H, C₆₋₁₀aryl or C₆₋₁₀heteroaryl, wherein the C₆₋₁₀aryl orC₆₋₁₀heteroaryl are optionally substituted with one to four R^(A1),wherein each R^(A1) is independently halo, C₁₋₆alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl, orC₁₋₄alkyl-O—C₁₋₄alkyl.

In some embodiments, R¹ is H, phenyl, pyridyl, pyridazine, pyrazine, orpyrimidine, wherein the phenyl, pyridyl, pyridazine, pyrazine, orpyrimidine is optionally substituted with one to four R^(A1), whereineach R^(A1) is independently halo, C₁₋₆alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl orC₁₋₄alkyl-O—C₁₋₄alkyl. In some embodiments, R¹ is phenyl, pyridyl,pyridazine, pyrazine, or pyrimidine, wherein the phenyl, pyridyl,pyridazine, pyrazine, or pyrimidine is optionally substituted with one,two, three, or four R^(A1), wherein each R^(A1) is independently halo,C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl,—O—C₃₋₆cycloalkyl or C₁₋₄alkyl-O—C₁₋₄alkyl. In some embodiments, R¹ isphenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, optionallysubstituted with one, two, three, or four R^(A1), wherein each R^(A1) isindependently halo, C₁₋₄alkyl, C₁₋₄haloalkyl, or —O—C₁₋₆alkyl. In someembodiments, R¹ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine,optionally substituted with one, two, three, or four R^(A1), whereineach R^(A1) is independently halo, C₁₋₄alkyl, or —O—C₁₋₄alkyl. In someembodiments, R¹ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine,optionally substituted with one, two, three, or four R^(A1), whereineach R^(A1) is independently halo or C₁₋₄alkyl. In some embodiments, R¹is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, optionallysubstituted with one, two, three, or four R^(A1), wherein each R^(A1) isindependently halo or —O—C₁₋₄alkyl. In some embodiments, R¹ is phenyl,pyridyl, pyridazine, pyrazine, or pyrimidine substituted with one, two,three, or four halogens. In some embodiments, R¹ is phenyl, pyridyl,pyridazine, pyrazine, or pyrimidine substituted with two or threehalogens. In some embodiments, R¹ is phenyl, pyridyl, pyridazine,pyrazine, or pyrimidine substituted with two or three halogens selectedfrom chloro and fluoro.

In some embodiments, R¹ is H, phenyl or pyridyl, wherein the phenyl orpyridyl is optionally substituted with one to four R^(A1), wherein eachR^(A1) is independently halo, C₁₋₄alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,cyano, —O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl or C₁₋₄alkyl-O—C₁₋₄alkyl. In someembodiments, R¹ is phenyl or pyridyl, wherein the phenyl or pyridyl isoptionally substituted with one, two, three, or four R^(A1), whereineach R^(A1) is independently halo, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl orC₁₋₄alkyl-O—C₁₋₄alkyl. In some embodiments, R¹ is phenyl or pyridyl,optionally substituted with one, two, three, or four R^(A1), whereineach R^(A1) is independently halo, C₁₋₄alkyl, C₁₋₆haloalkyl, or—O—C₁₋₆alkyl. In some embodiments, R¹ is phenyl or pyridyl, optionallysubstituted with one, two, three, or four R^(A1), wherein each R^(A1) isindependently halo, C₁₋₄alkyl, or —O—C₁₋₄alkyl. In some embodiments, R¹is phenyl or pyridyl, optionally substituted with one, two, three, orfour R^(A1), wherein each R^(A1) is independently halo or C₁₋₄alkyl. Insome embodiments, R¹ is phenyl or pyridyl, optionally substituted withone, two, three, or four R^(A1), wherein each R^(A1) is independentlyhalo or —O—C₁₋₄alkyl. In some embodiments, R¹ is phenyl or pyridylsubstituted with one, two, three, or four halogens. In some embodiments,R¹ is phenyl or pyridyl substituted with two or three halogens. In someembodiments, R¹ is phenyl or pyridyl substituted with two or threehalogens selected from chloro and fluoro.

In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, orVIIb, R¹ is H or a C₆₋₁₀aryl, wherein the C₆₋₁₀aryl is optionallysubstituted with one to four R^(A1), wherein each R^(A1) isindependently halo, C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano,—O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl or C₁₋₄alkyl-O—C₁₋₄alkyl. In someembodiments, R¹ is H or phenyl, wherein the phenyl is optionallysubstituted with one to four R^(A1), wherein each R^(A1) isindependently halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, cyano,—O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl or C₁₋₄alkyl-O—C₁₋₄alkyl. In someembodiments, R¹ is phenyl, optionally substituted with one, two, three,or four R^(A1), wherein each R^(A1) is independently halo, C₁₋₆alkyl,C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl orC₁₋₄alkyl-O—C₁₋₄alkyl. In some embodiments, R¹ is phenyl, optionallysubstituted with one, two, three, or four R^(A1), wherein each R^(A1) isindependently halo, C₁₋₄alkyl, C₁₋₄haloalkyl, or —O—C₁₋₆alkyl. In someembodiments, R¹ is phenyl, optionally substituted with one, two, three,or four R^(A1), wherein each R^(A1) is independently halo, C₁₋₆alkyl, or—O—C₁₋₄alkyl. In some embodiments, R¹ is phenyl, optionally substitutedwith one, two, three, or four R^(A1), wherein each R^(A1) isindependently halo or C₁₋₄alkyl. In some embodiments, R¹ is phenyl,optionally substituted with one, two, three, or four R^(A1), whereineach R^(A1) is independently halo or —O—C₁₋₄alkyl. In some embodiments,R¹ is phenyl substituted with one, two, three, or four halogens. In someembodiments, R¹ is phenyl substituted with two or three halogens. Insome embodiments, R¹ is phenyl substituted with two or three halogensselected from chloro and fluoro.

In some embodiments, R¹ is selected from the group consisting of

In some embodiments, R¹ is selected from the group consisting of:

In some embodiments, R¹ is selected from the group consisting of

In some embodiments, R¹ is pyridyl, optionally substituted with one,two, three, or four R^(A1), wherein each R^(A1) is independently halo,C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl,—O—C₃₋₆cycloalkyl or C₁₋₄alkyl-O—C₁₋₄alkyl. In some embodiments, R¹ ispyridyl, optionally substituted with one, two, three, or four R^(A1),wherein each R^(A1) is independently halo, C₁₋₄alkyl, C₁₋₄haloalkyl, or—O—C₁₋₄alkyl. In some embodiments, R¹ is pyridyl, optionally substitutedwith one, two, three, or four R^(A1), wherein each R^(A1) isindependently halo, C₁₋₄alkyl, or —O—C₁₋₄alkyl. In some embodiments, R¹is pyridyl, optionally substituted with one, two, three, or four R^(A1),wherein each R^(A1) is independently halo or C₁₋₆alkyl. In someembodiments, R¹ is pyridyl, optionally substituted with one, two, three,or four R^(A1), wherein each R^(A1) is independently halo or—O—C₁₋₄alkyl. In some embodiments, R¹ is pyridyl substituted with one,two, three, or four halogens. In some embodiments, R¹ is pyridylsubstituted with two or three halogens. In some embodiments, R¹ ispyridyl substituted with two or three halogens selected from chloro andfluoro.

In some embodiments, the compound of Formula I, IL, III, IV, VI, or VII,has a Formula VIII:

-   -   wherein p is 2 or 3.

In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa,IV, IVa, VI, VIa, VII, or VIIa, has a Formula VIIIa:

-   -   wherein p is 2 or 3.

In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb,IV, IVb, VI, VIb, VII, or VIIb, has a Formula VIIIb:

-   -   wherein p is 2 or 3.

In some embodiments, for the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, or VIIIb, each R^(A1) is independently halo,C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl,—O—C₃₋₆cycloalkyl or C₁₋₄alkyl-O—C₁₋₄alkyl. In some embodiments, eachR^(A1) is independently halo, C₁₋₆alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,cyano, —O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl or C₁₋₆alkyl-O—C₁₋₄alkyl. In someembodiments, each R^(A1) is independently halo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl orC₁₋₄alkyl-O—C₁₋₄alkyl. In some embodiments, each R^(A1) is independentlyhalo, C₁₋₄alkyl, C₁₋₄haloalkyl, or —O—C₁₋₄alkyl. In some embodiments,each R^(A1) is independently halo, C₁₋₄alkyl, or —O—C₁₋₆alkyl. In someembodiments, each R^(A1) is independently halo, C₁₋₄alkyl, cyano, or—O—C₁₋₆alkyl. In some embodiments, each R^(A1) is independently halo,cyano, or C₁₋₄alkyl. In some embodiments, each R^(A1) is independentlyhalo or C₁₋₄alkyl. In some embodiments, each R^(A1) is independentlyhalo, cyano, or —O—C₁₋₄alkyl. In some embodiments, each R^(A1) isindependently halo or —O—C₁₋₄alkyl. In some embodiments, each R^(A1) isindependently a halogen. In some embodiments, each R^(A1) isindependently chloro or fluoro.

In some embodiments, for the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, or VIIIb, R^(4a), R^(4b), R^(5a), R^(5b), R^(8a),R^(8b), R^(9a) and R^(9b) are each independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, halo, hydroxyl, cyano, —O—C₁₋₄alkyl, orC₁₋₄alkylene-O—C₁₋₄alkyl. In some embodiments, R^(4a), R^(4b), R^(5a),R^(5b), R^(8a), R^(8b), R^(9a) and R^(9b) are each independently H,C₁-C₆ alkyl, halo, or cyano. In some embodiments, R^(4a), R^(4a),R^(5a), R^(5b), R^(8a), R^(8b), R^(9a) and R^(9b) are each independentlyH, halo, or C₁-C₄ alkyl. In some embodiments, R^(4a), R^(4b), R^(5a),R^(5b), R^(8a), R^(8b), R^(9a) and R^(9b) are each independently H,fluoro, chloro, or C₁-C₄ alkyl. In some embodiments, R^(4a), R^(4b),R^(5a), R^(5b), R^(8a), R^(8b), R^(9a) and R^(9b) are each independentlyH or cyano. In some embodiments, R^(4a), R^(4b), R^(5a), R^(5b), R^(6a),R^(6b), R^(9a) and R^(9b) are each independently H or C₁₋₄haloalkyl.

In some embodiments, for the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, or VIIIb, any one of (i) R^(4a) and R^(4b), (ii)R^(5a) and R^(5b), (iii) R^(8a) and R^(8b), or (iv) R^(9a) and R^(9b)together with the carbon atom to which they are attached form a (i) 3 to7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ringcontaining 1 to 2 heteroatoms selected from N, O, and S, wherein the 3to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ringis optionally substituted with one to three R^(A3), wherein each R^(A3)is independently oxo, halo, cyano, C₁₋₄alkyl, C₃₋₆cycloalkyl or —OR^(e).In some embodiments, any one of (i) R^(4a) and R^(4b), (ii) R^(5a) andR^(5b), (iii) R^(8a) and R^(8b), or (iv) R^(9a) and R^(9b) together withthe carbon atom to which they are attached form a (i) 3 to 7 memberedcarbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 memberedcarbocyclic ring or the 4 to 7 membered heterocyclic ring is optionallysubstituted with one to three R^(A3), wherein each R^(A3) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In someembodiments, any one of (i) R^(4a) and R^(4b), (ii) R^(5a) and R^(5b),(iii) R^(8a) and R^(8b), or (iv) R^(9a) and R^(9b) together with thecarbon atom to which they are attached form a 3 to 7 memberedcarbocyclic ring, wherein the 3 to 7 membered carbocyclic ring isoptionally substituted with one to three R^(A3), wherein each R^(A3) isindependently oxo, halo, cyano, C₁₋₆alkyl, or C₃₋₆cycloalkyl. In someembodiments, any one of (i) R^(4a) and R^(4b), (ii) R^(5a) and R^(5b),(iii) R^(8a) and R^(8b), or (iv) R^(9a) and R^(9b) together with thecarbon atom to which they are attached form a 4 to 7 memberedheterocyclic ring containing 1 or 2 heteroatoms selected from N, O, andS, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 memberedheterocyclic ring is optionally substituted with one to three R^(A3),wherein each R^(A3) is independently oxo, halo, cyano, C₁₋₆alkyl, orC₃₋₆cycloalkyl. In some embodiments, any one of (i) R^(4a) and R^(4b),(ii) R^(5a) and R^(5b), (iii) R^(8a) and R^(8b), or (iv) R^(9a) andR^(9b) together with the carbon atom to which they are attached form a(i) 3 to 7 membered carbocyclic ring or a (ii) 3 to 7 memberedheterocyclic ring containing 1 or 2 heteroatoms selected from N, O, andS. In some embodiments, any one of (i) R^(4a) and R^(4b), (ii) R^(5a)and R^(5b), (iii) R^(8a) and R^(8b), or (iv) R^(9a) and R^(9b) togetherwith the carbon atom to which they are attached form a 3 memberedcarbocyclic ring optionally substituted with one to three R^(A3),wherein each R^(A3) is independently oxo, halo, cyano, C₁₋₆alkyl, orC₃₋₆cycloalkyl. In some embodiments, any one of (i) R^(4a) and R^(4b),(ii) R^(5a) and R^(5b), (iii) R^(8a) and R^(8b), or (iv) R^(9a) andR^(9b) together with the carbon atom to which they are attached form a 3to 7 membered carbocyclic ring. In some embodiments, R^(4a) and R^(4b)together with the carbon atom to which they are attached form a 3membered carbocyclic ring optionally substituted with one to threeR^(A3), wherein each R^(A3) is independently oxo, halo, cyano,C₁₋₆alkyl, or C₃₋₆cycloalkyl. In some embodiments R^(5a) and R^(5b)together with the carbon atom to which they are attached form a 3membered carbocyclic ring optionally substituted with one to threeR^(A3), wherein each R^(A3) is independently oxo, halo, cyano,C₁₋₆alkyl, or C₃₋₆cycloalkyl. In some embodiments, R^(8a) and R^(8b)together with the carbon atom to which they are attached form a 3membered carbocyclic ring optionally substituted with one to threeR^(A3), wherein each R^(A3) is independently oxo, halo, cyano,C₁₋₆alkyl, or C₃₋₆cycloalkyl. In some embodiments, R^(9a) and R^(9b)together with the carbon atom to which they are attached form a 3membered carbocyclic ring optionally substituted with one to threeR^(A3), wherein each R^(A3) is independently oxo, halo, cyano,C₁₋₆alkyl, or C₃₋₆cycloalkyl. In some embodiments, R^(4a) and R^(4b)together with the carbon atom to which they are attached form a 3membered carbocyclic ring. In some embodiments R^(5a) and R^(5b)together with the carbon atom to which they are attached form a 3membered carbocyclic ring. In some embodiments, R^(8a) and R^(8b)together with the carbon atom to which they are attached form a 3membered carbocyclic ring. In some embodiments, R^(9a) and R^(9b)together with the carbon atom to which they are attached form a 3membered carbocyclic ring.

In some embodiments, for the compounds of Formula VI, VIa, VIb, VII,VIIa, VIIb, VIII VIIIa or VIIIb, m is 0, 1, or 2. In some embodiments, mis 0. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, for the compounds of Formula VI, VIa, VIb, VII,VIIa, VIIb, VIII VIIIa or VIIIb, each R² is independently C₁₋₆alkyl,C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),—CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NHR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or two R² on same carbon atomtogether with the carbon atom to which they both are attached form a 3to 7 membered carbocyclic ring wherein the 3 to 7 membered carbocyclicring is optionally substituted with one to three R^(A2), wherein eachR^(A2) is independently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or—OR^(e).

In some embodiments, for the compounds of Formula VI, VIa, VIb, VII,VIIa, VIIb, VII, VIIIa or VIIIb, each R² is independently C₁₋₆alkyl,C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),—CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NHR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or R^(2a) and R^(2b) or twoR² on same carbon atom together with the carbon atom to which they bothare attached form a 3-5 membered carbocyclic ring wherein the 3-5membered carbocyclic ring is optionally substituted with one to threeR^(A2), wherein each R^(A2) is independently oxo, halo, cyano,C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, for the compounds of Formula VI, VIa, VIb, VII,VIIa, VIIb, VIII, VIIIa or VIIIb, each R² is independently C₁₋₄alkyl,C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),—CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NHR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—; —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or two R² on same carbon atomtogether with the carbon atom to which they both are attached form a 3membered carbocyclic ring, wherein the 3 membered carbocyclic ring isoptionally substituted with one to three R^(A2), wherein each R^(A2) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl or —OR^(e).

In some embodiments, for the compounds of Formula VI, VIa, VIb, VII,VIIa, VIIb, VIII, VIIIa or VIIb, each R² is independently C₁₋₆alkyl,C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a),—CH₂—S(O)_(n)R^(a)—, —OR^(a), —O—C(O)—NHR^(a), —NHR^(a)—,—C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—,—S(O)_(n)—NH(R^(a))—, or —S(O)_(n)—R^(a)—; or two R² on same carbon atomtogether with the carbon atom to which they both are attached form a 3membered carbocyclic ring.

In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa or VIIIb, each R² is independently C₁₋₆alkyl,C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a), —OR^(a) or—NHR^(a). In some embodiments, each R² is independently C₁₋₆alkyl,C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a), or —OR^(a). In someembodiments, each R² is independently C₁₋₆alkyl, C₃₋₆cycloalkyl, orhalo. In some embodiments, each R² is independently halo. In someembodiments, each R² is independently —C(O)—NH(R^(a))—,—NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—, —S(O)_(n)—NH(R^(a))—,—S(O)_(n)—R^(a)—, or —O—C(O)—NHR^(a). In some embodiments, each R² isindependently —OR^(a), —NHR^(a), C(O)—NH(R^(a)), NR^(e)—C(O)R^(a), or—NR^(e)—S(O)_(n)R^(a). In some embodiments, each R² is independently—OR^(a), or —O—C(O)—NHR^(a). In some embodiments, each R² isindependently —S(O) NH(R^(a)), or —S(O)_(n)—R^(a)—; In some embodiments,each R² is independently halo, cyano, —NHR^(a)— or —OR^(a). In someembodiments, each R² is —NHR^(a). In some embodiments, each R² isindependently is halo, cyano, or —OR^(a). In some embodiments, each R²is cyano. In some embodiments, each R² is independently —OR^(a). In someembodiments, each R² is independently —OR and each R^(a) isindependently C₃-C₆ cycloalkyl optionally substituted optionallysubstituted with 1 to 2 substituents independently selected from thegroup consisting of halo, cyano, and —O—C₁-C₄alkyl. In some embodiments,each R² is independently —OR^(a); wherein each R^(a) is independentlyC₁-C₆ alkyl optionally substituted with 1 to 2 substituentsindependently selected from the group consisting of halo, cyano,—O—C₁-C₄ alkyl. In some embodiments, each R² is independently —OR^(a);wherein each R^(a) is independently C₁-C₆ alkyl optionally substitutedwith a —O—C₁₋₄alkyl or halo. In some embodiments, each R² isindependently —OR^(a); wherein each R^(a) is independently C₁-C₆ alkyloptionally substituted with a —O—C₁₋₄alkyl.

In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa or VIIIb, m is 2 and each R² is independentlyC₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a), —OR^(a)or —NHR^(a). In some embodiments, m is 2 and each R² is independentlyC₁₋₆alkyl, C₃₋₆cycloalkyl, halo, cyano, —CH₂R^(a)—, —CH₂OR^(a), or—OR^(a). In some embodiments, m is 2 and each R² is independentlyC₁₋₆alkyl, C₃₋₆cycloalkyl, or halo. In some embodiments, m is 2 and eachR² is independently halo. In some embodiments, m is 2 and each R² isindependently —C(O)—NH(R^(a))—, —NR^(e)—C(O)R^(a)—,—NR^(e)—S(O)_(n)R^(a)—, —S(O)_(n)—NH(R^(a))—, —S(O)_(n)—R^(a)—, or—O—C(O)—NHR^(a). In some embodiments, m is 2 and each R² isindependently-OR^(a), —NHR^(a)—, —C(O)—NH(R^(a)), —NR^(e)—C(O)R^(a), or—NR^(e)—S(O)_(n)R^(a). In some embodiments, m is 2 and each R² isindependently-OR^(a), or —O—C(O)—NHR^(a). In some embodiments, m is 2and each R² is independently —S(O)_(n)—NH(R^(a)), or —S(O)_(n)—R^(a)—.In some embodiments, m is 2 and each R² is independently halo, cyano,—NHR^(a)— or —OR^(a). In some embodiments, m is 2 and each R² isindependently —NHR^(a). In some embodiments, m is 2 and each R² isindependently is halo, cyano, or —OR^(a). In some embodiments, m is 2and each R² is cyano. In some embodiments, m is 2 and each R² isindependently a halo. In some embodiments, m is 2 and each R² isindependently —OR^(a). In some embodiments, m is 2 and each R² isindependently —OR^(a) and each R^(a) is independently C₃-C₆ cycloalkyloptionally substituted optionally substituted with 1 to 2 substituentsindependently selected from the group consisting of halo, cyano, and—O—C₁-C₄alkyl. In some embodiments, m is 2 and each R² is independently—OR^(a); wherein each R^(a) is independently C₁-C₆ alkyl optionallysubstituted with 1 to 2 substituents independently selected from thegroup consisting of halo, cyano, —O—C₁-C₄ alkyl. In some embodiments, mis 2 and each R² is independently —OR^(a); wherein each R^(a) isindependently C₁-C₆ alkyl optionally substituted with a —O—C₁₋₄alkyl orhalo. In some embodiments, each m is 2 and R² is independently —OR^(a);wherein each R^(a) is independently C₁-C₆ alkyl optionally substitutedwith a —O—C₁₋₄alkyl.

In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa or VIIIb, m is 1 and R² is C₁₋₆alkyl, C₃₋₆cycloalkyl,halo, cyano, —CH₂R^(a)—, —CH₂OR^(a), —OR^(a) or —NHR^(a). In someembodiments, m is 1 and R² is C₁₋₄alkyl, C₃₋₆cycloalkyl, halo, cyano,—CH₂R^(a)—, —CH₂OR^(a), or —OR^(a). In some embodiments, m is 1 and R²is C₁₋₆alkyl, C₃₋₆cycloalkyl, or halo. In some embodiments, m is 1 andR² is halo. In some embodiments, m is 1 and R² is —C(O)—NH(R^(a))—,—NR^(e)—C(O)R^(a)—, —NR^(e)—S(O)_(n)R^(a)—, —S(O)_(n)—NH(R^(a))—,—S(O)_(n)—R^(a)—, or —O—C(O)—NHR^(a). In some embodiments, m is 1 and R²is —OR^(a), —NHR^(a), —C(O)—NH(R^(a)), —NR^(e)—C(O)R^(a), or—NR^(e)—S(O)_(n)R^(a). In some embodiments, m is 1 and R² is —OR^(a), or—O—C(O)—NHR^(a). In some embodiments, m is 1 and R² is—S(O)_(n)—NH(R^(a)), or —S(O)_(n)—R^(a)—. In some embodiments, m is 1and R² is halo, cyano, —NHR^(a)— or —OR^(a). In some embodiments, m is 1and R² is —NHR^(a). In some embodiments, m is 1 and R² is halo, cyano,or —OR^(a). In some embodiments, m is 1 and R² is cyano. In someembodiments, m is 1 and R² is halo. In some embodiments, m is 1 and R²is —OR^(a). In some embodiments, m is 1 and R² is —OR^(6a) and R^(6b) isC₃-C₆ cycloalkyl optionally substituted optionally substituted with 1 to2 substituents independently selected from the group consisting of halo,cyano, and —O—C₁-C₄alkyl. In some embodiments, m is 1 and R² is —OR^(a);wherein R^(a) is C₁-C₆ alkyl optionally substituted with 1 to 2substituents independently selected from the group consisting of halo,cyano, —O—C₁-C₄ alkyl. In some embodiments, m is 1 and R² is —OR^(a);wherein R^(a) is C₁-C₆ alkyl optionally substituted with a —O—C₁₋₄alkylor halo. In some embodiments, each m is 1 and R² is —OR^(a); whereineach R^(a) is C₁-C₆ alkyl optionally substituted with a —O—C₁₋₆alkyl.

In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa or VIIIb, m is 1 or 2, each R² is independently haloor —OR^(a), and each R^(a) is independently H or C₁-C₆ alkyl. In someembodiments, m is 1 or 2, each R² is independently halo or —OR^(a), andeach R^(a) is independently H or C₁-C₃ alkyl. In some embodiments, m is1 or 2, each R² is independently halo or —OR^(a), and each R^(a) isindependently H or methyl. In some embodiments, m is 1 or 2, each R² isindependently halo or —OR^(a), and each R^(a) is H. In some embodiments,m is 1 or 2, each R² is independently halo or —OR^(a), and each R^(a) ismethyl.

In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa or VIIIb, m is 1, R² is halo or —OR^(a), and R^(a) isH or C₁-C₆ alkyl. In some embodiments, m is 1, R² is halo or —OR^(a),and R^(a) is H or C₁-C₃ alkyl. In some embodiments, m is 1, R² is haloor —OR^(a), and R^(a) is H or methyl. In some embodiments, m is 1, R² ishalo or —OR^(a), and R^(a) is H. In some embodiments, m is 1, R² is haloor —OR^(a), and R^(a) is methyl.

In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa or VIIIb, m is 2, each R² is independently halo or—OR^(a), and each R^(a) is independently H or C₁-C₆ alkyl. In someembodiments, m is 2, each R² is independently halo or —OR^(a), and eachR is independently H or C₁-C₃ alkyl. In some embodiments, m is 2, eachR² is independently halo or —OR^(a), and each R^(a) is independently Hor methyl. In some embodiments, m is 2, each R² is independently halo or—OR^(a), and each R^(a) is H. In some embodiments, m is 2, each R² isindependently halo or —OR^(a), and each R^(a) is methyl.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, and VIIIb, each R^(a) is independently H, C₁₋₄alkyl,or C₃₋₆cycloalkyl; wherein the C₁₋₆alkyl or C₃₋₆cycloloalkyl isoptionally substituted with 0 to 4 substituents independently selectedfrom the group consisting of halo, cyano, —O—C₁₋₄alkyl, 5 to 10 memberedcarbocyclic ring, 5 to 10 membered heterocyclic ring containing 1 or 2heteroatom selected from N, O, and S, 6 to 10 membered aromatic ring,and 5 to 10 membered heteroaromatic ring containing 1 or 3 heteroatomsselected from N, O and S, wherein the 5 to 10 membered carbocyclic ring,5 to 10 membered heterocyclic ring, the 6 to 10 membered aromatic ring,or the 5 to 10 membered heteroaromatic ring is optionally substitutedwith one to four R^(A5), wherein each R^(A5) is independently oxo, halo,cyano, C₁₋₆alkyl, C₁₋₆cycloloalkyl or —OR^(e).

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, and VIIIb, each R^(a) is independently H, C₁-C₆alkyl, or C₃₋C₆ cycloalkyl optionally substituted with 1 to 2substituents independently selected from the group consisting of halo,cyano, —O—C₁-C₄ alkyl, 5 to 10 membered carbocyclic ring, and 5 to 10membered heterocyclic ring containing 1 or 2 heteroatoms selected fromN, O and S.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, and VIIIb, each R^(a) is independently H, C₁-C₄alkyl, or C₃-C₆ cycloalkyl optionally substituted with 1 to 2substituents independently selected from the group consisting of halo,cyano, and —O—C₁-C₄ alkyl.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, and VIIIb, each R^(a) is independently C₃-C₆cycloalkyl optionally substituted optionally substituted with 1 to 2substituents independently selected from the group consisting of halo,cyano, and —O—C₁-C₄alkyl.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIb, VIII, VIIIa, and VIIIb, each R^(a) is independently C₁-C₆ alkyloptionally substituted with 1 to 2 substituents independently selectedfrom the group consisting of halo, cyano, —O—C₁-C₄ alkyl.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, III, IIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, and VIIIb, each R^(a) is independently C₁₋₆alkyloptionally substituted with a —O—C₁₋₄alkyl or halo.

In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa,IIb, ILI, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, and VIIIb, each R^(a) is independently a 5 to 10membered carbocyclic ring, 5 to 10 membered heterocyclic ring containing1 or 2 heteroatom selected from N, O, and S, a 6 to 10 membered aromaticring, or a 5 to 10 membered heteroaromatic ring containing 1 or 3heteroatoms selected from N, O and S, wherein the 5 to 10 memberedcarbocyclic ring, 5 to 10 membered heterocyclic ring, the 6 to 10membered aromatic ring, or the 5 to 10 membered heteroaromatic ring isoptionally substituted with one to four R^(A4), wherein each R^(A4) isindependently oxo, halo, cyano, C₁₋₆alkyl, C₁₋₆cycloloalkyl or —OR^(e).

In some embodiments of the compound of Formula I, Ia, Ib, II, IIa, IIb,ILI, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb,VIII, VIIIa, and VIIIb, each R^(e) is independently H, C₁₋₆alkyl orC₃₋₆cycloalkyl wherein each C₁₋₆alkyl or C₃₋₆cycloalkyl is optionallysubstituted by a halo or a cyano. In some embodiments, each R^(e) isindependently H, C₁₋₆alkyl or C₃₋₆cycloalkyl. In some embodiments, eachR^(e) is independently H or C₁₋₄alkyl wherein the C₁₋₄alkyl isoptionally substituted by a halo or a cyano. In some embodiments, eachR^(e) is independently H or C₃₋₆cycloalkyl wherein each C₃₋₆cycloalkylis optionally substituted by a halo or a cyano. In some embodiments,each R^(e) is independently H or C₁₋₆alkyl. In some embodiments, eachR^(e) is independently H or C₃₄cycloalkyl. In some embodiments, eachR^(e) is H. In some embodiments, each R^(e) is independently C₁₋₄alkyl.In some embodiments, each R^(e) is independently C₃₋₆cycloalkyl.

In some embodiments, for the compounds of Formula VIII, VIIIa, and VIIb,p is 2 or 3 and each R^(A1) is independently halo, C₁₋₆alkyl,C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, —O—C₁. 4alkyl, —O—C₃₋₆cycloalkylor C₁₋₄alkyl-O—C₁₋₄alkyl. In some embodiments, p is 2 or 3 and eachR^(A1) is independently halo, C₁₋₄alkyl, C₁₋₄haloalkyl, or —O—C₁₋₄alkyl.In some embodiments, p is 2 or 3 and each R^(A1) is independently halo,C₁₋₄alkyl, or —O—C₁₋₄alkyl. In some embodiments, p is 2 or 3 and eachR^(A1) is independently halo or C₁₋₄alkyl. In some embodiments, p is 2or 3 each R^(A1) is independently halo or —O—C₁₋₄alkyl. In someembodiments, p is 2 or 3 and each R^(A1) is independently a halogen. Insome embodiments, p is 2 or 3 and each R^(A1) is independently selectedfrom chloro and fluoro.

In some embodiments, for the compounds of Formula VIII, VIIIa, and VIIb,p is 2 and each R^(A1) is independently halo, C₁₋₆alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl orC₁₋₆alkyl-O—C₁₋₄alkyl. In some embodiments, p is 2 and each R^(A1) isindependently halo, C₁₋₄alkyl, C₁₋₆haloalkyl, or —O—C₁₋₆alkyl. In someembodiments, p is 2 and each R^(A1) is independently halo, C₁₋₄alkyl, or—O—C₁₋₄alkyl. In some embodiments, p is 2 and each R^(A1) isindependently halo or C₁₋₄alkyl. In some embodiments, p is 2 and eachR^(A1) is independently halo or —O—C₁₋₄alkyl. In some embodiments, p is2 and each R^(A1) is independently a halogen. In some embodiments, p is2 and each R^(A1) is independently selected from chloro and fluoro.

In some embodiments, for the compounds of Formula VIII, VIIIa, and VIIb,p is 3 and each R^(A1) is independently halo, C₁₋₆alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, cyano, —O—C₁₋₄alkyl, —O—C₃₋₆cycloalkyl orC₁₋₄alkyl-O—C₁₋₄alkyl. In some embodiments, p is 3 and each R^(A1) isindependently halo, C₁₋₄alkyl, C₁₋₆haloalkyl, or —O—C₁₋₄alkyl. In someembodiments, p is 3 and each R^(A1) is independently halo, C₁₋₄alkyl, or—O—C₁₋₄alkyl. In some embodiments, p is 3 and each R^(A1) isindependently halo or C₁₋₄alkyl. In some embodiments, p is 3 and eachR^(A1) is independently halo or —O—C₁₋₄alkyl. In some embodiments, p is3 and each R^(A1) is independently a halogen. In some embodiments, p is3 and each R^(A1) is independently selected from chloro and fluoro.

In some embodiments of the compounds of Formula IV, IVa, or IVb:

-   -   X is —CR^(8a)R^(8b)—;    -   W¹ is a bond or —CR^(4a)R^(4b)—;    -   W² is —CR^(5a)R^(5b)— or —CR^(6a)═CR^(6a)—;        -   Z is —CR^(9a)R^(9b)—;    -   L is —CH₂—;        -   R^(2a), R^(2b), R^(12a), and R^(12b) are independently H,            C₁₋₆alkyl, halo, —OR^(a)—, or —CH₂OR^(a);            -   R^(a) is H or C₁₋₆alkyl;        -   R^(4a), R^(4b), R^(5a), R^(5b), R^(8a), R^(8b), R^(9a),            R^(9b) are independently H, hydroxyl, C₁₋₆alkyl, or            —O—C₁₋₄alkyl;        -   both R^(6a) and R^(6b) are H and        -   R¹ is C₆₋₁₀aryl optionally substituted with one to four            R^(A1), wherein each R^(A1) is independently fluoro or            chloro.

In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VIII VIIa, VIb,VIII VIIIa, or VIIIb, is a compound selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII VIIa, VIIb,VIII VIIIa, or VIIIb, is a compound selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb,VIII, VIIIa, or VIIIb, is a compound selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.

III. Compositions and Kits

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are alsopharmaceutical compositions that comprise one or more of the compoundsprovided herein or pharmaceutically acceptable salts, isomer, or amixture thereof and one or more pharmaceutically acceptable vehiclesselected from carriers, adjuvants and excipients. The compounds providedherein may be the sole active ingredient or one of the activeingredients of the pharmaceutical compositions. Suitablepharmaceutically acceptable vehicles may include, for example, inertsolid diluents and fillers, diluents, including sterile aqueous solutionand various organic solvents, permeation enhancers, solubilizers andadjuvants. Such compositions are prepared in a manner well known in thepharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, MacePublishing Co., Philadelphia, Pa. 17th Ed. (1985); and ModernPharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes,Eds.).

In one aspect, provided herein are pharmaceutical compositionscomprising a compound provided herein (e.g., a compound of Formula I,Ia, Ib, II, IIa, Ib, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa,VIb, VII, VIIa, VIb, VIII, VIIIa, or VIIIb), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient orcarrier. In some embodiments, the pharmaceutical compositions comprise atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient or carrier.

In some embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more (e.g., one, two, three, four, one or two,one to three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical compositions further comprise a therapeutically effectiveamount of the one or more (e.g., one, two, three, four, one or two, oneto three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof.

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical compositions may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In some embodiments, the pharmaceutical compositionsmay be administered by intra-arterial injection, intravenously,intraperitoneally, parenterally, intramuscularly, subcutaneously,orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds provided herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound provided herein orpharmaceutically acceptable salts, isomer, or a mixture thereof, theactive ingredient (such as a compound provided herein) is usuallydiluted by an excipient and/or enclosed within such a carrier that canbe in the form of a capsule, sachet, paper or other container. When theexcipient serves as a diluent, it can be in the form of a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the pharmaceutical compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols(as a solid or in a liquid medium), ointments containing, for example,up to 10% by weight of the active compound, soft and hard gelatincapsules, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose or any combinations thereof. The pharmaceutical compositionscan additionally include lubricating agents such as talc, magnesiumstearate, and mineral oil; wetting agents; emulsifying and suspendingagents; preserving agents such as methyl and propylhydroxy-benzoates;sweetening agents; and flavoring agents; or any combinations thereof.

The pharmaceutical compositions that include at least one compounddescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof can be formulated so as to provide quick, sustained ordelayed release of the active ingredient (such as a compound providedherein) after administration to the subject by employing proceduresknown in the art.

Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present disclosure employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds provided herein in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof. When referring to these preformulationcompositions as homogeneous, the active ingredient may be dispersedevenly throughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with materials such as shellac, cetyl alcohol, andcellulose acetate.

Pharmaceutical compositions for inhalation or insufflation may includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof, and powders. The liquid or solidcompositions may contain suitable pharmaceutically acceptable excipientsas described supra. In some embodiments, the compositions areadministered by the oral or nasal respiratory route for local orsystemic effect. In other embodiments, compositions in pharmaceuticallyacceptable solvents may be nebulized by use of inert gases. Nebulizedsolutions may be inhaled directly from the nebulizing device or thenebulizing device may be attached to a facemask tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions may be administered, preferably orally or nasally, fromdevices that deliver the formulation in an appropriate manner.

In one aspect, provided herein are kits that comprise a compoundprovided herein, (e.g., a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb,VIII, VIIIa, or VIIIb), or a pharmaceutically acceptable salt,stereoisomer, prodrug, or solvate thereof, and suitable packaging. Insome embodiments, the kit further comprises instructions for use. Insome embodiments, the kit comprises a compound provided herein (e.g., acompound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa,IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb),or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvatethereof, and a label and/or instructions for use of the compounds in thetreatment of the indications, including the diseases or conditions,described herein.

In some embodiments, the kits further comprise one or more (e.g., one,two, three, four, one or two, one to three, or one to four) additionaltherapeutic agents, or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are articles of manufacture that comprisea compound described herein or pharmaceutically acceptable salts,isomer, or a mixture thereof in a suitable container. In someembodiments, the container may be a vial, jar, ampoule, preloadedsyringe, or intravenous bag.

IV. Methods

In one embodiment, methods of treating an HIV (e.g., HIV-1 and/or HIV-2)infection in a human having or at risk of having the infectioncomprising administering to the human a therapeutically effective amountof a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV,IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, orVIIIb, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of a compound of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable saltthereof, are provided.

In some embodiments, the methods further comprise administering to thehuman a therapeutically effective amount of one, two, three, or fouradditional therapeutic agents. In certain embodiments, the additionaltherapeutic agent or agents are anti-HIV agents. In particularembodiments, the additional therapeutic agent or agents are HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors,gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsidpolymerization inhibitors, HIV bNAbs (broadly neutralizing HIVantibodies), TLR7 agonists, pharmacokinetic enhancers, other drugs fortreating HIV, or combinations thereof. In one embodiment, the additionaltherapeutic agent or agents are abacavir, tenofovir alafenamide,tenofovir disoproxil,N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide,or a pharmaceutically acceptable salt thereof.

In another embodiment, a use of a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII,VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition of a compound of Formula I, Ia,Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa,VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceuticallyacceptable salt thereof, for treating an HIV (e.g., HIV-1 and/or HIV-2)infection in a human having or at risk of having the infection isprovided.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb,VIII, VIIIa, or VIb, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of a compound of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable saltthereof, for use in medical therapy is provided.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb,VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition of Formula I, Ia, Ib, II, IIa, IIb, III,IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb,VIII, VIIIa, or VIIIb, or pharmaceutically acceptable salt thereof, foruse in treating an HIV infection is provided.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VIII VIIa, VIb,VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition of a compound of Formula I, Ia, Ib, II, Ha,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, or VIIb, or a pharmaceutically acceptable saltthereof for use in a method of treating an HIV infection in a humanhaving or at risk of having the infection, is provided.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIb,VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition of a compound of Formula I, Ia, Ib, II, Ha,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIa,VIIb, VIII, VIIIa, or VIIb, or a pharmaceutically acceptable saltthereof for use in a method of treating an HIV infection in a humanhaving or at risk of having the infection, is provided wherein saidmethod further comprises administering to the human one, two, three, orfour additional therapeutic agents.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIb,VII, VIIIa, or VIb, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of a compound of Formula I, Ia, Ib, II, Ha,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIa,VIIb, VIII, VIIIa, or VIIb, or a pharmaceutically acceptable saltthereof for use in a method of treating an HIV infection in a humanhaving or at risk of having the infection, is provided wherein saidmethod further comprises administering to the human one, two, three, orfour additional therapeutic agents selected from the group consisting ofHIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitorsof reverse transcriptase, HIV nucleoside or nucleotide inhibitors ofreverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents,capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists,pharmacokinetic enhancers, other drugs for treating HIV, or combinationsthereof. In one embodiment, the one, two, three, or four additionaltherapeutic agents are selected from HIV protease inhibitors, HIVnon-nucleoside inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, latency reversingagents, HIV capsid inhibitors, HIV bNAbs, TLR7 agonists, andcombinations thereof.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VIII VIIa, VIb,VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition of a compound of Formula I, Ia, Ib, II, Ha,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable saltthereof for use in a method of treating an HIV infection in a humanhaving or at risk of having the infection, is provided wherein saidmethod further comprises administering to the human a therapeuticallyeffective amount of tenofovir disoproxil and emtricitabine.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIb,VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition of a compound of Formula I, Ia, Ib, II, Ha,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIa,VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable saltthereof for use in a method of treating an HIV infection in a humanhaving or at risk of having the infection, is provided wherein saidmethod further comprises administering to the human a therapeuticallyeffective amount of tenofovir alafenamide and emtricitabine.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIb,VII, VIIIa, or VIb, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of a compound of Formula I, Ia, Ib, II, Ha,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIa,VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable saltthereof for use in a method of treating an HIV infection in a humanhaving or at risk of having the infection, is provided wherein saidmethod further comprises administering to the human a therapeuticallyeffective amount of tenofovir disoproxil.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, Ib,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb,VII, VIIIa, or VIb, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of a compound of Formula I, Ia, Ib, II, Ha,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable saltthereof for use in a method of treating an HIV infection in a humanhaving or at risk of having the infection, is provided wherein saidmethod further comprises administering to the human a therapeuticallyeffective amount of tenofovir alafenamide.

In another embodiment, a method of using a compound of Formula I, Ia,Ib, II, IIa, IIb, III, Ia, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb,VII VIIa, VIIb, VIII, VIIIa, or VIIIb in therapy is provided. Inparticular, a method of treating the proliferation of the HIV virus,treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal(e.g., a human) is provided, comprising administering to the mammal acompound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa,IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIb, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In another embodiment, a composition comprising a compound of Formula I,Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa,VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient,for use in a method of treating the proliferation of the HIV virus,treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal(e.g., a human) is provided.

In one embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb, III,IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb,VIII, VIIIa, or VIb, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of a compound of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa,VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable saltthereof, is provided for use in preventing HIV infection.

For example, in one embodiment, a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII,VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition of a compound of Formula I, Ia,Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa,VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceuticallyacceptable salt thereof, is provided for use in pre-exposure prophylaxis(PrEP), i.e., before the exposure of the individual to the HIV virus toprevent HIV infection from taking hold if the individual is exposed tothe virus and/or to keep the virus from establishing a permanentinfection and/or to prevent the appearance of symptoms of the diseaseand/or to prevent the virus from reaching detectable levels in theblood.

In another embodiment, the use of a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII,VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for treating an HIVinfection in a human being having or at risk of having the infection isdisclosed.

In another embodiment, the use of a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII,VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable saltthereof, as a research tool is disclosed.

In another embodiment, an article of manufacture comprising acomposition effective to treat an HIV infection; and packaging materialcomprising a label which indicates that the composition can be used totreat infection by HIV is disclosed. Exemplary compositions comprise acompound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa,IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, ora pharmaceutically acceptable salt thereof.

In still another embodiment, a method of inhibiting the replication ofHIV is disclosed. The method comprises exposing the virus to aneffective amount of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb,VIII, VIIIa, or VIIIb, or a salt thereof, under conditions wherereplication of HIV is inhibited.

In another embodiment, the use of a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII,VIIa, VIIb, VIII, VIIIa, or VIIIb, to inhibit the activity of the HIVintegrase enzyme is disclosed.

In another embodiment, the use of a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII,VIIa, VIIb, VIII, VIIIa, or VIIIb, or a salt thereof, to inhibit thereplication of HIV is disclosed.

V. Administration

The compounds of the present disclosure (also referred to herein as theactive ingredients), can be administered by any route appropriate to thecondition to be treated. Suitable routes include oral, rectal, nasal,topical (including buccal and sublingual), transdermal, vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural), and the like. It will beappreciated that the preferred route may vary with, for example, thecondition of the recipient. An advantage of certain compounds disclosedherein is that they are orally bioavailable and can be dosed orally.

A compound of the present disclosure may be administered to anindividual in accordance with an effective dosing regimen for a desiredperiod of time or duration, such as at least about one month, at leastabout 2 months, at least about 3 months, at least about 6 months, or atleast about 12 months or longer. In some embodiments, the compound isadministered on a daily or intermittent schedule for the duration of theindividual's life.

The specific dose level of a compound of the present disclosure for anyparticular subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound described herein per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate.In some embodiments, about 0.1 and 100 mg/kg may be appropriate. Inother embodiments a dosage of between 0.5 and 60 mg/kg may beappropriate. Normalizing according to the subject's body weight isparticularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compounddescribed herein administered per dose or per day. Daily dosage of acompound of Formula I, Ia, Ib, II, IIa, Ib, III, IIIa, IIIb, IV, IVa,IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIb, VIII, VIIIa, or VIIIb, ora pharmaceutically acceptable salt or pharmaceutically acceptabletautomer thereof, may be between about 1 mg and 4,000 mg, between about2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day,or between about 15 to 150 mg/day.

The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgmentof the administering physician.

The compounds of the present disclosure may be administered to anindividual (e.g., a human) in a therapeutically effective amount. Insome embodiments, the compound is administered once daily.

The compounds provided herein can be administered by any useful routeand means, such as by oral or parenteral (e.g., intravenous)administration. Therapeutically effective amounts of the compound mayinclude from about 0.00001 mg/kg body weight per day to about 10 mg/kgbody weight per day, such as from about 0.0001 mg/kg body weight per dayto about 10 mg/kg body weight per day, or such as from about 0.001 mg/kgbody weight per day to about 1 mg/kg body weight per day, or such asfrom about 0.01 mg/kg body weight per day to about 1 mg/kg body weightper day, or such as from about 0.05 mg/kg body weight per day to about0.5 mg/kg body weight per day. In some embodiments, a therapeuticallyeffective amount of the compounds provided herein include from about 0.3mg to about 30 mg per day, or from about 30 mg to about 300 mg per day,or from about 0.3 μg to about 30 mg per day, or from about 30 μg toabout 300 μg per day.

A compound of the present disclosure may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound ofthe present disclosure (e.g., from 1 mg to 1000 mg of compound).Therapeutically effective amounts may include from about 0.1 mg per doseto about 1000 mg per dose, such as from about 50 mg per dose to about500 mg per dose, or such as from about 100 mg per dose to about 400 mgper dose, or such as from about 150 mg per dose to about 350 mg perdose, or such as from about 200 mg per dose to about 300 mg per dose, orsuch as from about 0.01 mg per dose to about 1000 mg per dose, or suchas from about 0.01 mg per dose to about 100 mg per dose, or such as fromabout 0.1 mg per dose to about 100 mg per dose, or such as from about 1mg per dose to about 100 mg per dose, or such as from about 1 mg perdose to about 10 mg per dose, or such as from about 1 mg per dose toabout 1000 mg per dose. Other therapeutically effective amounts of thecompound of Formula I, IL, Ha, IIb, III, Ia, IIIb, IV, IVa, IVb, V, Va,Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb are about 1 mgper dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose.Other therapeutically effective amounts of the compound of the presentdisclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325,350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675,700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about1000 mg per dose.

In some embodiments, the methods described herein comprise administeringto the subject an initial daily dose of about 1 to 500 mg of a compoundp herein and increasing the dose by increments until clinical efficacyis achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used toincrease the dose. The dosage can be increased daily, every other day,twice per week, once per week, once every two weeks, once every threeweeks, or once a month.

When administered orally, the total daily dosage for a human subject maybe between about 1 mg and 1,000 mg, between about 10-500 mg/day, betweenabout 50-300 mg/day, between about 75-200 mg/day, or between about100-150 mg/day. In some embodiments, the total daily dosage for a humansubject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or1000 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 200, 300, 400, 500,600, 700, or 800 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about300, 400, 500, or 600 mg/day administered in a single dose.

In some embodiments, the total daily dosage for a human subject may beabout 100 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 150 mg/dayadministered in a single dose. In some embodiments, the total dailydosage for a human subject may be about 200 mg/day administered in asingle dose. In some embodiments, the total daily dosage for a humansubject may be about 250 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 300mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 350 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 400 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 450mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 500 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 550 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 600mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 650 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 700 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 750mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 800 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 850 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 900mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 950 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 1000 mg/day administered in a single dose.

A single dose can be administered hourly, daily, weekly, or monthly. Forexample, a single dose can be administered once every 1 hour, 2, 3, 4,6, 8, 12, 16 or once every 24 hours. A single dose can also beadministered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. Asingle dose can also be administered once every 1 week, 2, 3, or onceevery 4 weeks. In certain embodiments, a single dose can be administeredonce every week. A single dose can also be administered once everymonth. In some embodiments, a compound disclosed herein is administeredonce daily in a method disclosed herein. In some embodiments, a compounddisclosed herein is administered twice daily in a method disclosedherein.

The frequency of dosage of the compound of the present disclosure willbe determined by the needs of the individual patient and can be, forexample, once per day or twice, or more times, per day. Administrationof the compound continues for as long as necessary to treat the HBVinfection, HIV infection, cancer, hyper-proliferative disease, or anyother indication described herein. For example, a compound can beadministered to a human being infected with HBV for a period of from 20days to 180 days or, for example, for a period of from 20 days to 90days or, for example, for a period of from 30 days to 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of the compound of thepresent disclosure followed by a period of several or more days duringwhich a patient does not receive a daily dose of the compound. Forexample, a patient can receive a dose of the compound every other day,or three times per week. Again by way of example, a patient can receivea dose of the compound each day for a period of from 1 to 14 days,followed by a period of 7 to 21 days during which the patient does notreceive a dose of the compound, followed by a subsequent period (e.g.,from 1 to 14 days) during which the patient again receives a daily doseof the compound. Alternating periods of administration of the compound,followed by non-administration of the compound, can be repeated asclinically required to treat the patient.

The compounds of the present disclosure or the pharmaceuticalcompositions thereof may be administered once, twice, three, or fourtimes daily, using any suitable mode described above. Also,administration or treatment with the compounds may be continued for anumber of days; for example, commonly treatment would continue for atleast 7 days, 14 days, or 28 days, for one cycle of treatment. Treatmentcycles are well known in cancer chemotherapy, and are frequentlyalternated with resting periods of about 1 to 28 days, commonly about 7days or about 14 days, between cycles. The treatment cycles, in otherembodiments, may also be continuous.

VI. Combination Therapy

In certain embodiments, a method for treating or preventing an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, one or two, or one tothree) additional therapeutic agents. In one embodiment, a method fortreating an HIV infection in a human having or at risk of having theinfection is provided, comprising administering to the human atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents.

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more (e.g., one, two, three, one or two, or oneto three) additional therapeutic agents, and a pharmaceuticallyacceptable carrier, diluent, or excipient are provided.

In certain embodiments, the present disclosure provides a method fortreating an HIV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents which are suitable for treating an HIV infection.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four, or more additional therapeutic agents. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four, or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

Administration of HIV Combination Therapy

In certain embodiments, a compound disclosed herein is administered withone or more additional therapeutic agents. Co-administration of acompound disclosed herein with one or more additional therapeutic agentsgenerally refers to simultaneous or sequential administration of acompound disclosed herein and one or more additional therapeutic agents,such that therapeutically effective amounts of the compound disclosedherein and the one or more additional therapeutic agents are bothpresent in the body of the patient. When administered sequentially, thecombination may be administered in two or more administrations.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents. For example, thecompound disclosed herein may be administered within seconds, minutes,or hours of the administration of the one or more additional therapeuticagents. In some embodiments, a unit dose of a compound disclosed hereinis administered first, followed within seconds or minutes byadministration of a unit dose of one or more additional therapeuticagents.

Alternatively, a unit dose of one or more additional therapeutic agentsis administered first, followed by administration of a unit dose of acompound disclosed herein within seconds or minutes. In otherembodiments, a unit dose of a compound disclosed herein is administeredfirst, followed, after a period of hours (e.g., 1-12 hours), byadministration of a unit dose of one or more additional therapeuticagents. In yet other embodiments, a unit dose of one or more additionaltherapeutic agents is administered first, followed, after a period ofhours (e.g., 1-12 hours), by administration of a unit dose of a compounddisclosed herein.

In certain embodiments, a compound disclosed herein is combined with oneor more additional therapeutic agents in a unitary dosage form forsimultaneous administration to a patient, for example as a solid dosageform for oral administration.

In certain embodiments, a compound of Formula I is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HIV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HIV, such as HIV protease inhibitors, HIVnon-nucleoside or non-nucleotide inhibitors of reverse transcriptase,HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, HIV non-catalytic site (or allosteric) integraseinhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

HIV Combination Therapy

In the above embodiments, the additional therapeutic agent may be ananti-HIV agent. HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, immunomodulators,immunotherapeutic agents, antibody-drug conjugates, gene modifiers, geneeditors (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases,synthetic nucleases, TALENs), cell therapies (such as chimeric antigenreceptor T-cell, CAR-T, and engineered T cell receptors, TCR-T,autologous T cell therapies), latency reversing agents, compounds thattarget the HIV capsid, immune-based therapies, phosphatidylinositol3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors,IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators,protein disulfide isomerase inhibitors, complement C5a receptorantagonists, DNA methyltransferase inhibitor, HIV vif gene modulators,Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors,TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinasemodulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicinginhibitors, Rev protein inhibitors, integrin antagonists, nucleoproteininhibitors, splicing factor modulators, COMM domain containing protein 1modulators, CD4 modulators, CD4 antagonists, HIV ribonuclease Hinhibitors, retrocyclin modulators, CDK-9 inhibitors, CCR5 chemokineantagonists, CCR5 gene modulators, dendritic ICAM-3 grabbing nonintegrin1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors,hyaluronidase inhibitors, Nef antagonists, Nef inhibitors,Protease-activated receptor-1 antagonists, TNF alpha ligand inhibitors,PDE4 inhibitors, Complement Factor H modulators, ubiquitin ligaseinhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinaseinhibitors, proprotein convertase PC9 stimulators, ATP dependent RNAhelicase DDX3X inhibitors, reverse transcriptase priming complexinhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers,HIV gene therapy, HIV vaccines, and combinations thereof.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of combination drugs for HIV, other drugs fortreating HIV, HIV protease inhibitors, HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIVmaturation inhibitors, latency reversing agents, capsid inhibitors,immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecificantibodies, and “antibody-like” therapeutic proteins, and combinationsthereof.

HIV Combination Drugs

Examples of combination drugs include ATRIPLA® (efavirenz, tenofovirdisoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir,emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®;rilpivirine, tenofovir disoproxil fumarate, and emtricitabine);STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, andemtricitabine); TRUVADA® (tenofovir disoproxil fumarate andemtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide andemtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENRVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofoviralafenamide hemifumarate, emtricitabine, and cobicistat); SYMFITM(efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDUTM(lamivudine and tenofovir disoproxil fumarate); tenofovir andlamivudine; tenofovir alafenamide and emtricitabine; tenofoviralafenamide hemifumarate and emtricitabine; tenofovir alafenamidehemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamidehemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR®(zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavirsulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir andritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR®(abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavirand cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfateand ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine;dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavirsulfate, and lamivudine; lamivudine, nevirapine, and zidovudine;raltegravir and lamivudine; doravirine, lamivudine, and tenofovirdisoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil;dapivirine+levonorgestrel, dolutegravir+lamivudine,dolutegravir+emtricitabine+tenofovir alafenamide,elsulfavirine+emtricitabine+tenofovir disoproxil,lamivudine+abacavir+zidovudine, lamivudine+abacavir,lamivudine+tenofovir disoproxil fumarate,lamivudine+zidovudine+nevirapine, lopinavir+ritonavir,lopinavir+ritonavir+abacavir+lamivudine,lopinavir+ritonavir+zidovudine+lamivudine, tenofovir+lamivudine, andtenofovir disoproxil fumarate+emtricitabine+rilpivirine hydrochloride,lopinavir, ritonavir, zidovudine and lamivudine.

Other HIV Drugs

Examples of other drugs for treating HIV include acemannan, alisporivir,astodrimer, BanLec, CC-11050, deferiprone, Gamimune, griffithsin,metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, Vorapaxar, VSSP,H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazFgene therapy, MK-8527, BlockAide, PSC-RANTES, ABX-464, AG-1105,APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100,IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040(PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110,TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

HIV Protease Inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir,brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir,indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate,ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657(PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911.

HIV Reverse Transcriptase Inhibitors

Examples of HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase include dapivirine, delavirdine, delavirdine mesylate,doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine,rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, andelsulfavirine (VM-1500).

Examples of HIV nucleoside or nucleotide inhibitors of reversetranscriptase include adefovir, adefovir dipivoxil, azvudine,emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine,apricitabine, censavudine, didanosine, elvucitabine, festinavir,fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine,OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir,lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafoviretalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500 andKP-1461.

HIV Integrase Inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin,derivatives of curcumin, chicoric acid, derivatives of chicoric acid,3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid,aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeicacid phenethyl ester, derivatives of caffeic acid phenethyl ester,tyrphostin, derivatives of tyrphostin, quercetin, derivatives ofquercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567,BMS-986197, cabotegravir (long-acting injectable), diketo quinolin-4-1derivatives, integrase-LEDGF inhibitor, ledgins, M-522, M-532,NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172,NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169, VM-3500 andcabotegravir.

Examples of HIV non-catalytic site, or allosteric, integrase inhibitors(NCINI) include CX-05045, CX-05168, and CX-14442.

HIV Entry Inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003(BMS-599793), gp120 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc,cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc(TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66,polypeptide C25P, TD-0680, and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide,BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusioninhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer andsifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADAanalogs.

Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38,BanLec, bentonite-based nanomedicine, fostemsavir tromethamine,IQP-0831, and BMS-663068.

Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide,and vMIP (Haimipu).

HIV Maturation Inhibitors

Examples of HIV maturation inhibitors include BMS-955176, BMS-986197,GSK-3640254 and GSK-2838232.

Latency Reversing Agents

Examples of latency reversing agents include histone deacetylase (HDAC)inhibitors, proteasome inhibitors such as velcade, and ixazomib citrate,protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4(BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid, orsuberoyl, anilide, and hydroxamic acid), IL-15 modulating antibodies,JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such aslargazole analogs, APH-0812, and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat, andpanobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B,and DAG-lactones.

Capsid Inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitorsor capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitorssuch as azodicarbonamide, HIV p24 capsid protein inhibitors, GS-6207,AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series.

Immune-Based Therapies

Examples of immune-based therapies include toll-like receptorsmodulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9,tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1)modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine);proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b;interferon alfa-n3; pegylated interferon alfa; interferon gamma;hydroxyurea; mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (PEI);gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107,interleukin-15/Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255,NKTR-262, NKTR-214, normferon, peginterferon alfa-2a, peginterferonalfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STINGmodulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103.

Examples of TLR agonists: vesatolimod (GS-9620), GS-986, IR-103,lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100,cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463,GS-9688, LHC-165, BDB-001, RG-7854, telratolimod.RO-7020531.

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib,CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib,perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib,rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439,CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577,GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666,RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857,VS-5584, XL-765, and ZSTK-474.

Alpha-4/Beta-7 Antagonists

Examples of Integrin alpha-4/beta-7 antagonists include PTG-100,TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV Antibodies, Bispecific Antibodies, and “Antibody-Like” TherapeuticProteins

Examples of HIV antibodies, bispecific antibodies, and “antibody-like”therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®,TandAbs®, Fab derivatives, bispecific antibodies, trispecificantibodies, multivalent antibodies, bnABs (broadly neutralizing HIV-1antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41,antibody-recruiting Molecules targeting HIV, anti-CD63 monoclonalantibodies, CD3 bispecific antibodies, CD16 bispecific antibodies,anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies,anti-Nef single domain antibodies, anti-Rev antibody, camelid derivedanti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001,gp140 targeted antibodies, gp41-based HIV therapeutic antibodies, humanrecombinant mAbs (PGT-121), ibalizumab, Immuglo, MB-66.

Examples of those targeting HIV in such a manner include bavituximab,UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117,3BNC117-LS, 3BNC60, D1D2, 10-1074, 10-1074-LS, GS-9722, DH411-2, BG18,PGT145, PGT121, PGT122, PGT-151, PGT-133, PGT-135, PGT-128, MDXO10(ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9,N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PG9,PG16, 8ANC195, 2Dm2m, 4Dm2m, 6Dm2m, VRC-01, VRC-01-LS, PGDM1400, A32,7B2, 10E8, 10E8VLS, 3810109, 10E8v4, 10E8.4/iMab,VRC-01/PGDM-1400/10E8v4, IMC-HIV, iMabm36, 10E8v4/PGT121-VRCO1, eCD4-Ig,IOMA, CAP256-VRC26.25, DRVIA7, SAR-441236, VRC-07-523, VRC07-523LS,VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, and VRC07. Examples ofHIV bispecific antibodies include MGD014, TMB-bispecific.

Example of in vivo delivered bnABs such as AAV8-VRC07; mRNA encodinganti-HIV antibody VRC01.

Pharmacokinetic Enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

Additional Therapeutic Agents

Examples of additional therapeutic agents include the compoundsdisclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (GileadSciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (GileadSciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (GileadSciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (GileadSciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (Universityof Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380(Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO2013/091096 (Boehringer Ingelheim).

HIV Vaccines

Examples of HIV vaccines include peptide vaccines, recombinant subunitprotein vaccines, live vector vaccines using viral vectors such asarenavirus, lymphocytic choriomeningitis virus (LCMV), pichinde virus,modified vaccinia Ankara virus (MVA), adenovirus, adeno-associated virus(AAV), vesicular stomatitis virus (VSV) and Chimpanzee adenovirus(ChAd), DNA vaccines, CD4-derived peptide vaccines, vaccinecombinations, BG505 SOSIP.664 gp140, rgp120 (AIDSVAX), ALVAC HIV,(vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype Cvaccine, Remune, ITV-1, Contre Vir, Ad4-Env145NFL, Ad5-ENRVA-48, HB-500,DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, Vacc-CRX, VVX-004, VAC-3S,multiclade DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A/B/Cvaccine, Pennvax-G, Pennvax-GP/MVA-CMDR, HIV-TriMix-mRNA vaccine,HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3NSSP ISA-51, poly-ICLC adjuvantedvaccines, TatImmune, GTU-multiHIV (FIT-06), gpl40[delta]V2.TVI+MF-59,rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV,TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123,rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env CladeC+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101,CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env,Ad26.Mod.HIV vaccine, Ad26.Mod.HIV+MVA mosaic vaccine+gp140, AGS-004,AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300,IHV-001, and virus-like particle vaccines such as pseudovirion vaccine,CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, HIVgag/pol/nef/env DNA vaccine, anti-TAT HIV vaccine, conjugatepolypeptides vaccine, dendritic-cell vaccines, gag-based DNA vaccine,GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i-key/MHCclass II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5,multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMVvector HIV gag vaccine, recombinant peptide vaccine (HIV infection),NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine,TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+romidepsin,variant gp120 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine,DNA.HTI, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP,INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer based vaccine,PD-201401, env (A, B, C, A/E)/gag (C) DNA Vaccine, gp120 (A,B,C,A/E)protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine(GLA-SE adjuvanted), HIV p24gag prime-boost plasmid DNA vaccine,arenavirus vector-based immunotherapies (Vaxwave, TheraT), MVA-BN HIV-1vaccine regimen, MVA.tHIVconsv4, MVA.tHIVconsv3, UBI HIV gp120, mRNAbased prophylactic vaccines, TBL-1203HI, VRC-HIVRGP096-00-VP, VAX-3S,and HIV MAG DNA vaccine.

HIV Combination Therapy

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from ATRIPLA®(efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA®(EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, andemtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovirdisoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxilfumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamideand emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENRVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat;emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxilfumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate;TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir,abacavir sulfate, and lamivudine; raltegravir; raltegravir andlamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir andritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavirsulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine;rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavirand cobicistat; darunavir and cobicistat; atazanavir; atazanavirsulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate andritonavir; darunavir; lamivudine; prolastin; fosamprenavir;fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavirmesylate; interferon; didanosine; stavudine; indinavir; indinavirsulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir;saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir;delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine andtenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine;abacavir; and abacavir sulfate.

It will be appreciated by one of skill in the art that the additionaltherapeutic agents listed above may be included in more than one of theclasses listed above. The particular classes are not intended to limitthe functionality of those compounds listed in those classes.

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase and an HIVnon-nucleoside inhibitor of reverse transcriptase. In another specificembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, and an HIV proteaseinhibiting compound. In an additional embodiment, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withan HIV nucleoside or nucleotide inhibitor of reverse transcriptase, anHIV non-nucleoside inhibitor of reverse transcriptase, and apharmacokinetic enhancer. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withat least one HIV nucleoside inhibitor of reverse transcriptase, anintegrase inhibitor, and a pharmacokinetic enhancer. In anotherembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two HIV nucleoside ornucleotide inhibitors of reverse transcriptase.

In some embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is used in combination with a HIV capsidinhibitor and/or a nucleoside reverse transcriptase translocationinhibitor. In some embodiments a compound disclosed herein is used incombination with lenacapavir and/or islatravir. In some embodiments acompound disclosed herein is used in combination with lenacapavir. Insome embodiments a compound disclosed herein is used in combination withislatravir.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofoviralafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide, or tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofabacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxilfumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate,and a second additional therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting oftenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and asecond additional therapeutic agent, wherein the second additionaltherapeutic agent is emtricitabine.

A compound as disclosed herein (e.g., any compound of Formula I) may becombined with one or more additional therapeutic agents in any dosageamount of the compound of Formula I (e.g., from 1 mg to 500 mg ofcompound).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30,or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 10 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide,and 200 mg emtricitabine. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with25 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Acompound as disclosed herein (e.g., a compound of Formula I) may becombined with the agents provided herein in any dosage amount of thecompound (e.g., from 1 mg to 500 mg of compound) the same as if eachcombination of dosages were specifically and individually listed.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 200-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400,350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil, and 200 mgemtricitabine. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 300 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. A compound as disclosedherein (e.g., a compound of Formula I) may be combined with the agentsprovided herein in any dosage amount of the compound (e.g., from 1 mg to500 mg of compound) the same as if each combination of dosages werespecifically and individually listed.

In one embodiment, kits comprising a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with one ormore (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents are provided.

Birth Control (Contraceptive) Combination Therapy

Therapeutic agents used for birth control (contraceptive) includecyproterone acetate, desogestrel, dienogest, drospirenone, estradiolvalerate, ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate,levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol,mifepristone, misoprostol, nomegestrol acetate, norelgestromin,norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersoneacetate, ulipristal acetate, and any combinations thereof.

Gene Therapy and Cell Therapy

Gene Therapy and Cell Therapy including the genetic modification tosilence a gene; genetic approaches to directly kill the infected cells;the infusion of immune cells designed to replace most of the patient'sown immune system to enhance the immune response to infected cells, oractivate the patient's own immune system to kill infected cells, or findand kill the infected cells; genetic approaches to modify cellularactivity to further alter endogenous immune responsiveness against theinfection.

Examples of dendritic cell therapy include AGS-004.

Example of CCR5 gene editing drugs such as SB-728T.

Example of CCR5 gene inhibitors such as Cal-1.

C34-CCR5/C34-CXCR4 expressing CD4-positive T cells.

AGT-103-transduced autologous T cell therapy.

AAV-eCD4-Ig gene therapy.

Gene Editors

The genome editing system is selected from the group consisting of: aCRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, ahoming endonucleases system, and a meganuclease system.

Examples of HIV targeting CRISPR/Cas9 systems include EBT-101.

CAR-T Cell Therapy

A population of immune effector cells engineered to express a chimericantigen receptor (CAR), wherein the CAR comprises an HIV antigen-bindingdomain. The HIV antigen include an HIV envelope protein or a portionthereof, gp120 or a portion thereof, a CD4 binding site on gp120, theCD4-induced binding site on gp120, N glycan on gp120, the V2 of gp120,the membrane proximal region on gp41. The immune effector cell is a Tcell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, aCD8+ T cell, or a combination thereof. Cells can be autologous orallogeneic.

Examples of HIV CAR-T include VC-CAR-T, anti-CD4 CART cell therapy,autologous hematopoietic stem cells genetically engineered to express aCD4 CAR and the C46 peptide.

TCR-T Cell Therapy

TCR-T cells are engineered to target HIV derived peptides present on thesurface of virus-infected cells.

VII. Examples

Exemplary chemical entities of the present disclosure are provided inthe specific examples that follow. Those skilled in the art willrecognize that, to obtain the various compounds herein, startingmaterials may be suitably selected so that the ultimately desiredsubstituents will be carried through the reaction scheme with or withoutprotection as appropriate to yield the desired product. Alternatively,it may be necessary or desirable to employ, in the place of theultimately desired substituent, a suitable group that may be carriedthrough the reaction scheme and replaced as appropriate with the desiredsubstituent.

Furthermore, one of skill in the art will recognize that thetransformations shown in the schemes below may be performed in any orderthat is compatible with the functionality of the particular pendantgroups.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

In the following description of the Examples, specific embodiments aredescribed. These embodiments are described in sufficient detail toenable those skilled in the art to practice certain embodiments of thepresent disclosure. Other embodiments may be utilized and logical andother changes may be made without departing from the scope of thedisclosure. The following description is, therefore, not intended tolimit the scope of the present disclosure.

Example 1: Preparation of((6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1)

Step 1. Synthesis of tert-butyl 3-amino-3-cyanoazepane-1-carboxylate(1a)

tert-Butyl 3-oxoazepane-1-carboxylate (3.5 g, 16.4 mmol), potassiumcyanide (1.60 g, 24.6 mmol), ammonium chloride (1.32 g, 24.6 mmol) inammonium hydroxide (19.5 mL), ethanol (20 mL) and water (6.5 mL) wereheated at 60° C. overnight. Reaction mixture was concentrated to ˜30 mL,and extracted with dichloromethane (3×). Combined organic layers werewashed with brine, dried (MgSO₄), filtered and purified by CombiFlash(80 g, ethyl acetate/hex) to give title compound. MS (m/z) 239.82[M+H]⁺.

Step 2: Synthesis of tert-butyl3-((tert-butoxycarbonyl)amino)-3-cyanoazepane-1-carboxylate (1b)

To a solution of tert-butyl 3-amino-3-cyano-azepane-1-carboxylate (1a,3.3 g, 13.8 mmol) in ethyl acetate (20 mL) was added saturated sodiumcarbonate (5 mL) and di-tert-butyl dicarbonate (4.51 g, 20.7 mmol).Reaction mixture was stirred for 2 days at room temperature. Reactionmixture was extracted with dichloromethane (3×), dried (MgSO₄), filteredand concentrated. Purification of the residue via CombiFlash (80 g,ethyl acetate/hexanes) gave title compound and recovered startingmaterial. MS (m/z) 339.9 [M+H]⁺.

Step 3: Synthesis of tert-butyl3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate (1c)

To a solution of tert-butyl3-((tert-butoxycarbonyl)amino)-3-cyanoazepane-1-carboxylate (1b, 0.952g, 2.81 mmol) in dichloromethane (14.0 mL) at 0° C. was addedbis(cyclopentadienyl) zirconium(IV) chloride hydride (1.45 g, 5.61mmol). Reaction mixture was stirred for 20 h at 0° C. Additionalbis(cyclopentadienyl)zirconium(IV) chloride hydride (1.45 g, 5.61 mmol)was added and reaction mixture was warmed to room temperature over 3hours. Reaction mixture was adsorbed onto silica gel, loaded into dryload cartridge and purified by CombiFlash (120 g, 0-30% EtOAc/Hex) togive title compound. MS (m/z) 342.73 [M+H]⁺.

Step 4: Synthesis of tert-butyl3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)vinyl)-3-((tert-butoxycarbonyl)amino)azepane-1-carboxylate(1d)

To a solution of methyl3-(benzyloxy)-6-((dimethoxyphosphoryl)methyl)-4-oxo-4H-pyran-2-carboxylate(prepared according to WO2018102485) (0.826 g, 2.16 mmol) in THF (15 mL)at −78° C. was added dropwise 1.0 M lithium diisopropylamide inTHF/hexanes (2.30 mL, 2.30 mmol). Reaction mixture was stirred for 60minutes, then a solution of tert-butyl3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate (1c, 0.370g, 1.08 mmol) in THF (5.0 mL) was added. Reaction mixture was stirredfor 0.5 hours at −78° C., then warmed to −40° C. After 1 hour, thereaction mixture was stirred at 0° C. for 4 hours. Reaction mixture wasquenched with 1 N HCl, brine was added and extracted with ethyl acetate(2×). Combined organic layers were dried (MgSO₄), filtered,concentrated, and purified by CombiFlash (120 g, 0-60% EtOAc/Hex) togive title compound. MS (m/z) 598.88 [M+H]⁺.

Step 5: Synthesis of tert-butyl3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)-3-((tert-butoxycarbonyl)amino)azepane-1-carboxylate(1e)

tert-Butyl3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)vinyl)-3-((tert-butoxycarbonyl)amino)azepane-1-carboxylate(1d, 490 mg, 0.80 mmol) and 20% palladium hydroxide on carbon, wet (114mg) in THF (20 mL) was stirred under hydrogen atmosphere (1 atm) for 1hour. Reaction mixture was filtered through a pad of Celite, washed withethyl acetate and concentrated to obtain tert-butyl3-((tert-butoxycarbonyl)amino)-3-(2-(5-hydroxy-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)azepane-1-carboxylate,which was used in next step without further purification.

tert-Butyl3-((tert-butoxycarbonyl)amino)-3-(2-(5-hydroxy-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)azepane-1-carboxylatefrom above (0.427 g) was dissolved in DMF (8 mL) and benzyl bromide (193μL, 1.63 mmol) and potassium carbonate (0.451 g, 3.26 mmol) were added.Reaction mixture was stirred for 2 hours. Reaction mixture was dilutedwith ethyl acetate, washed with 5% LiCl solution (3×) and brine, dried(MgSO₄), and filtered. Concentration and purification (40 g, 0-60%EtOAc/Hex) gave title compound. MS (m/z) 600.83 [M+H]⁺.

Step 6: Synthesis of11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(1f)

A solution of tert-butyl3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)-3-((tert-butoxycarbonyl)amino)azepane-1-carboxylate(1e, 0.252 g, 0.410 mmol) and trifluoroacetic acid (2.0 mL) indichloromethane (10.0 mL) was stirred at 0° C. for 2 hours, then warmedto room temperature over 4 hours. Reaction mixture was concentrated anddried under high vacuum overnight.

Methyl6-(2-(3-aminoazepan-3-yl)ethyl)-3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylatefrom above was dissolved in ethanol (10 mL) and heated at 90° C. for 5hours. Reaction mixture was concentrated and purified via CombiFlash (24g, 0-20% MeOH/CH₂Cl₂) to give title compound. MS (m/z) 351.28 [M+H]⁺.

Step 7: Synthesis of11-(benzyloxy)-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione

To a solution of11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (if, 260 mg, 0.626 mmol) in anhydrousmethanol (6.3 mL) was added 3-chloroperoxybenzoic acid (0.432 g, 2.51mmol), followed by N-iodosuccinimide (0.564 g, 2.51 mmol). Reactionmixture was heated at 70° C. for 15 minutes. Reaction mixture wasdiluted with dichloromethane and washed with 10% sodium sulfite. Aqueouslayer was back-extracted and combined organic layers were dried (MgSO₄),filtered and concentrated. Purification via CombiFlash (40 g, 0-10%MeOH/CH₂Cl₂) gave title compound. MS (m/z) 477.14 [M+H]⁺.

Step 8: Synthesis of11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1g)

To a solution of11-(benzyloxy)-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(210 mg, 0.441 mmol) in DMSO (6.5 mL) was added 2,4,6-trifluorobenzylamine (355 mg, 2.20 mmol), N,N-Diisopropylethylamine (384 μL, 2.20 mmol)and tetrakis(triphenylphosphine)palladium (25.5 mg, 0.022 mmol).Reaction mixture was degassed under vacuum and backfilled with CO (3×).Reaction mixture was slowly sparged with CO using 22 gauge needleconnected to a gas bag filled CO and heated at 80° C. for 4 hours.Reaction mixture was cooled to room temperature, diluted with ethylacetate, washed with 0.05 N HCl, saturated sodium bicarbonate solution,and brine, dried (MgSO₄), and concentrated. The residue was purified byCombiFlash (40 g, 0 to −100% EtOAc/Hex) to give desired product. MS(m/z) 538.15 [M+H]⁺.

Step 9: Resolution of(6aR)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1h-1) and(6aS)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1h-2)

Racemic11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(119 mg) was resolved using chiral SFC (IB, 30% MeOH).

(6aR)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide:Peak 1, MS (m/z) 538.16 [M+H]⁺.

(6aS)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide:Peak 2, MS (m/z) 538.18 [M+H]⁺.

Step 10: Synthesis of(6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1)

To a solution of(6aR)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1h-1, 37 mg, 0.069 mmol) in dichloromethane (1.5 mL) was addedtrifluoroacetic acid (1.0 mL). Reaction mixture was stirred at roomtemperature for 4 hours. Reaction mixture was aged in a freezer for 30hours. Reaction mixture was concentrated and purified by Gilson HPLC(Gemini 5-100% ACN/H₂O+0.1% TFA) to give title compound afterlyophilization. MS (m/z) 448.24 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ7.07-6.79 (m, 2H), 4.73-4.54 (m, 2H), 4.35 (dt, J=13.4, 8.0 Hz, 1H),3.98-3.73 (m, 3H), 3.49 (ddd, J=18.8, 11.2, 7.7 Hz, 1H), 3.19 (ddd,J=13.2, 7.0, 3.4 Hz, 1H), 2.31-2.07 (m, 3H), 2.07-1.85 (m, 3H), 1.79(dd, J=15.6, 6.9 Hz, 1H), 1.39-1.23 (m, 1H).

Example 2: Preparation of(6aS)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(2)

(6aS)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(2) was prepared in a manner similar to(6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1) except using(6aS)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1h-2) instead of(6aR)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1h-1) in Step 10. MS (m/z) 448.19 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 10.79 (t, J=5.0 Hz, 1H), 8.77 (s, 1H), 6.75-6.59 (m,2H), 4.65 (qd, J=14.4, 5.4 Hz, 2H), 4.44 (dt, J=13.7, 8.1 Hz, 1H), 4.10(dd, J=18.9, 8.3 Hz, 1H), 3.81-3.61 (m, 2H), 3.53 (ddd, J=19.0, 11.5,7.7 Hz, 1H), 3.14 (ddd, J=13.7, 7.2, 3.3 Hz, 1H), 2.15 (dddd, J=31.2,18.6, 11.4, 5.4 Hz, 4H), 1.83 (dddd, J=23.1, 16.1, 12.3, 5.0 Hz, 3H),1.42-1.26 (m, 1H).

Example 3: Preparation of(6aR)—N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(3)

(6aR)—N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(3) was prepared in a manner similar to(6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1) except using 2,4-drifluorobenzyl amine instead of2,4,6-trifluorobenzyl amine in Step 8. MS (m/z) 430.30 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 7.44 (q, J=8.4 Hz, 1H), 7.02-6.88 (m, 2H),4.68-4.54 (m, 2H), 4.37 (dt, J=13.6, 7.9 Hz, 1H), 3.99-3.74 (m, 3H),3.57-3.44 (m, 1H), 3.24-3.13 (m, 1H), 2.29-2.06 (m, 3H), 2.04-1.86 (m,3H), 1.86-1.72 (m, 1H), 1.32 (q, J=12.7, 12.2 Hz, 1H).

Example 4: Preparation of(6aS)—N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(4)

(6aS)—N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(4) was prepared in a manner similar to(6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1) except by using 2,4-drifluorobenzyl amine instead of2,4,6-trifluorobenzyl amine in Step 8 and(6aS)-11-(benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (1h-2) instead of(6aR)-11-(benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1h-1) in Step 10. MS (m/z) 430.31 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4)δ 7.44 (q, J=8.3 Hz, 1H), 7.05-6.87 (m, 2H), 4.68-4.55 (m, 2H), 4.37(dt, J=13.5, 8.0 Hz, 1H), 3.98-3.75 (m, 3H), 3.51 (ddd, J=18.7, 11.5,7.7 Hz, 1H), 3.24-3.14 (m, 1H), 2.30-2.09 (m, 3H), 2.09-1.86 (m, 3H),1.81 (dd, J=15.8, 6.5 Hz, 1H), 1.39-1.25 (m, 1H).

Example 5: Preparation(6aR)—N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(5)

(6aR)—N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(5) was prepared in a manner similar to(6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1) except by using 3-chloro-2-fluorobenzyl amine instead of2,4,6-trifluorobenzyl amine in Step 8. MS (m/z) 446.30 [M+H]⁺. ¹H NMR(400 MHz, Methanol-d4) δ 7.43-7.38 (m, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.14(t, J=7.8 Hz, 1H), 4.69 (dd, J=15.4, 5.3 Hz, 2H), 4.37 (dt, J=13.7, 8.1Hz, 1H), 3.98-3.74 (m, 3H), 3.58-3.44 (m, 1H), 3.20 (ddd, J=12.3, 7.0,3.7 Hz, 1H), 2.31-2.09 (m, 3H), 2.08-1.86 (m, 3H), 1.86-1.73 (m, 1H),1.32 (q, J=12.8, 12.4 Hz, 1H).

Example 6: Preparation of(6aS)—N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(6)

(6aS)—N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(6) was prepared in a manner similar to(6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1) except by using 3-chloro-2-fluorobenzyl amine instead of2,4,6-trifluorobenzyl amine in Step 8 and(6aS)-11-(benzyloxy)-N-(3-chloro-2-fluorobenzyl)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1h-2) instead of(6aR)-11-(benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1h-1) in Step 10. MS (m/z) 446.30 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4)δ 7.43-7.38 (m, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H),4.69 (dd, J=15.4, 5.3 Hz, 2H), 4.37 (dt, J=13.7, 8.1 Hz, 1H), 3.98-3.74(m, 3H), 3.58-3.44 (m, 1H), 3.20 (ddd, J=12.3, 7.0, 3.7 Hz, 1H),2.31-2.09 (m, 3H), 2.08-1.86 (m, 3H), 1.86-1.73 (m, 1H), 1.32 (q,J=12.8, 12.4 Hz, 1H).

Example 7: Preparation of((6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(7)

Step 1: Synthesis of methyl11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxylate(7a)

To a solution of7-benzyloxy-5-iodo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7-diene-6,9-dione (0.169 g, 0.355 mmol) in anhydroustetrahydrofuran (2.0 mL) and anhydrous methanol (2.0 mL) was addedN,N-diisopropylethylamine (185 μL, 1.06 mmol) andtetrakis(triphenylphosphine)palladium (0.021, 0.018 mmol). Reactionmixture was degassed under vacuum and backfilled with CO (3×). Reactionmixture was sparged with CO using 18 gauge needle connected to a gas bagfilled CO and heated at 65° C. for 18 hours. Additional methanol (4.0mL) and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.029 g, 0.0355 mmol) were added and reactionmixture was heated under CO atmosphere (1 atm) for 24 hours. Reactionmixture was cooled to room temperature, diluted with ethyl acetate andwashed with 0.05 N HCl, saturated sodium bicarbonate solution, brine anddried (MgSO₄) and concentrated. Crude product was purified by CombiFlash(40 g, 0 to −100% EtOAc/Hept) to give desired product. MS (m/z) 409.1[M+H]⁺.

Step 2: Synthesis of11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxylicacid (7b)

A solution of methyl11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxylate(7a) (46 mg, 0.113 mmol) and lithium hydroxide (5M, 68 μL, 0.338 mmol)in THF (1.0 mL) and methanol (0.5 mL) was heated at 45° C. for 2 hours.Reaction mixture was acidified with 1 M HCl and extracted with ethylacetate (3×). Combined organic layer was dried (MgSO₄), filtered andconcentrated to give desired product that was used in the next stepwithout further purification. MS (m/z) 395.05 [M+H]⁺.

Step 3: Synthesis of11-(benzyloxy)-1,10-dioxo-N′-(2-(2,4,6-trifluorophenyl)ethanethioyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carbohydrazide(7d)

To a solution of11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxylicacid (7b) (44 mg, 0.112 mmol) in anhydrous THF (2.0 mmol) was addedN-methyl morpholine (49 μL, 0.446 mmol) and isobutyl chloroformate (19μL, 0.145 mmol) at 0° C. Reaction mixture was stirred for 2 hours.2-(2,4,6-trifluorophenyl)ethanethiohydrazide, TFA salt (7c) (55.9 mg,0.167 mmol) was added, followed by N-methyl morpholine (49 μL, 0.446mmol). Reaction mixture was stirred for 1 hour. Reaction mixture wasdiluted with ethyl acetate, washed with saturated bicarbonate, dried(MgSO₄), filtered and concentrated. Reaction product was used in nextstep without further purification. MS (m/z) 596.93 [M+H]⁺.

Step 4: Synthesis of11-(benzyloxy-9-(5-(2,4,6-trifluorobenzyl)-1,3,4-thiadiazol-2-yl)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(7e)

11-(benzyloxy)-1,10-dioxo-N′-(2-(2,4,6-trifluorophenyl)ethanethioyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carbohydrazide(7d) (approximately 0.0033 mmol) was dissolved in acetic acid (1.5 mL)and heated at 100° C. for 7 hours. Reaction mixture was concentrated andpurified by Gilson HPLC (Gemini, 5-100% ACN/H2O+0.1% TFA) andlyophilized to give desired product. MS (m/z) 489.36 [M+H]⁺.

Step 5: Synthesis of11-hydroxy-9-(5-(2,4,6-trifluorobenzyl)-1,3,4-thiadiazol-2-yl)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(7)

A solution of7-benzyloxy-5-[5-[(2,4,6-trifluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7-diene-6,9-dione(7e) (1.5 mg, 0.0026 mmol) and trifluoroacetic acid (0.5 mL) in toluene(1.0 mL) was stirred at room temperature for 1.5 hours. Reaction mixturewas concentrated and purified by Gilson HPLC (Gemini, 5-100%ACN/H₂O+0.1% TFA) to give desired product after lyophilization. MS (m/z)579.04 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 7.05-6.88 (m, 2H), 4.52(s, 2H), 4.38 (dt, J=13.3, 8.1 Hz, 1H), 4.05 (dd, J=18.5, 7.6 Hz, 1H),3.96 (d, J=14.2 Hz, 1H), 3.86 (d, J=14.1 Hz, 1H), 3.67 (ddd, J=18.7,10.9, 8.0 Hz, 1H), 3.23 (dq, J=9.9, 3.5 Hz, 1H), 2.47-2.18 (m, 3H), 1.99(ddd, J=32.1, 14.1, 6.8 Hz, 3H), 1.83 (dd, J=13.7, 5.7 Hz, 1H), 1.33 (q,J=11.2, 10.7 Hz, 1H).

Example 8: Preparation of(6aS,8S)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(8-1) and(6aR,8R)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(8-2)

Step 1. Synthesis of11-(benzyloxy)-8-fluoro-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(8a)

To a solution of11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.050 g, 0.143 mmol), prepared according to the preparation ofintermediate if in Example 1, in THF (3 mL) under Ar (g) was addedN-fluorobenzenesulfonimide (0.135 g, 0.428 mmol). The reaction mixturewas cooled to −78° C. and a 1.0 M solution of LiHMDS in THF (0.428 mL,0.428 mmol) was added dropwise. After stirring for 0.5 h, the reactionwas warmed to room temperature and left to stir overnight. Methanol wasadded to quench and the solution was concentrated. The residue waspurified by column chromatography (0-20% MeOH/CH₂Cl₂) to provide11-(benzyloxy)-8-fluoro-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione.MS (m/z) 369.26 [M+H]⁺.

Step 2. Synthesis of11-(benzyloxy-8-fluoro-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(8b)

To a solution of11-(benzyloxy)-8-fluoro-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.022 g, 0.059 mmol) in anhydrous methanol (0.5 mL) was added 77%m-CPBA (meta-chloroperbenzoic acid) (0.053 g, 0.237 mmol) andN-iodosuccinimide (0.053 g, 0.237 mmol). The reaction mixture was heatedat 80° C. for 24 h and cooled to room temperature. The solution wasdiluted with CH₂Cl₂ and washed with 10% aqueous Na₂SO₃ solution. Theaqueous phase was extracted with CH₂Cl₂ and the combined organic phasewas dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by column chromatography (0-10% MeOH/CH₂Cl₂) to provide11-(benzyloxy)-8-fluoro-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione.MS (m/z) 495.10 [M+H]⁺.

Step 3. Synthesis of11-(benzyloxy)-8-fluoro-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(8e)

To a solution of11-(benzyloxy)-8-fluoro-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.026 g, 0.053 mmol) in DMSO (1 mL) was added2,4,6-trifluorobenzylamine (0.042 g, 0.263 mmol), i-Pr₂NEt (0.046 mL,0.263 mmol), and Pd(PPh₃)₄ (0.003 g, 0.003 mmol). The reaction flask wasevacuated and backfilled with CO (g) three times, then heated to 80° C.for 4 h under 1 atm of CO (g). After cooling to rt, the reaction wasdiluted with EtOAc and washed with 0.05 N HCl (1×), saturated aqueousNaHCO₃ (1×), and brine (1×). The organic phase was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography (0-100% EtOAc/heptane) to provide11-(benzyloxy)-8-fluoro-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide.MS (m/z) 556.17 [M+H]⁺.

Step 4. Synthesis of(6aS,8S)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(8-1) and(6aR,8R)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(8-2)

rac-(6aR,8S)-11-(benzyloxy)-8-fluoro-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamidewas separated into its individual enantiomers by preparative SFC on anAD-H column using 40% MeOH co-solvent to provide two separatedenantiomers. Each of the separated enantiomers was dissolved in 1:1toluene/TFA (2 mL). The reaction mixture was allowed to stir at rt for 2h and concentrated. The residue was dissolved in MeCN and purified bypreparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2 mm)eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30minutes. The combined fractions were lyophilized to afford the titlecompounds. Absolute configurations are not confirmed.

Peak 1: MS (m/z) 466.24 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (t,J=5.7 Hz, 1H), 7.30-7.16 (m, 2H), 6.84-6.69 (m, 1H), 4.61 (dd, J=14.5,5.8 Hz, 1H), 4.52 (dd, J=14.6, 5.5 Hz, 1H), 4.19 (dt, J=12.8, 7.4 Hz,1H), 3.86 (d, J=14.3 Hz, 1H), 3.68 (d, J=14.2 Hz, 1H), 3.05 (dt, J=12.3,5.7 Hz, 1H), 2.44 (d, J=2.9 Hz, 1H), 2.38 (s, 1H), 2.16-2.00 (m, 2H),1.83 (dd, J=15.6, 8.1 Hz, 2H), 1.74-1.65 (m, 1H), 1.24 (s, 1H). ¹⁹F NMR(376 MHz, DMSO-d₆) δ −109.31 (ddd, J=15.5, 9.3, 6.4 Hz), −112.48 (t,J=7.2 Hz), −167.67 (ddd, J=50.1, 35.0, 24.1 Hz).

Peak 2: MS (m/z) 466.27 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (t,J=5.7 Hz, 1H), 7.31-7.13 (m, 2H), 6.85-6.63 (m, 1H), 4.60 (dd, J=14.6,5.9 Hz, 1H), 4.51 (dd, J=14.5, 5.5 Hz, 1H), 4.19 (dt, J=14.0, 7.4 Hz,1H), 3.86 (d, J=14.3 Hz, 1H), 3.67 (d, J=14.2 Hz, 1H), 3.04 (dt, J=12.5,5.8 Hz, 1H), 2.44 (d, J=3.0 Hz, 1H), 2.40-2.29 (m, 1H), 2.16-1.98 (m,2H), 1.90-1.77 (m, 2H), 1.69 (d, J=16.1 Hz, 1H), 1.33-1.18 (m, 1H). ¹⁹FNMR (376 MHz, DMSO-d₆) δ −109.31 (tt, J=9.4, 6.4 Hz), −112.48 (t, J=7.2Hz), −167.67 (ddd, J=50.0, 35.1, 24.2 Hz).

Example 9: Preparation of(6aS,8R)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(9-1),(6aR,8R)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(9-2),(6aS,8S)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(9-3), and(6aR,8S)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(9-4)

Step 1. Synthesis of11-(benzyloxy)-8-hydroxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(9a)

A solution of11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.100 g, 0.285 mmol), prepared according to the preparation ofintermediate if in Example 1, in THF (5 mL) under Ar (g) was cooled to−78° C. A 1.0 M solution of LiHMDS in THF (0.856 mL, 0.856 mmol) wasadded dropwise. After 10 min, a solution of2-(benzenesulfonyl)-3-phenyl-oxaziridine (0.164 g, 0.628 mmol) in THF (1mL) was added. The reaction mixture was warmed to room temperature andleft to stir for 3 h. Methanol was added to quench and the solution wasconcentrated. The residue was purified by column chromatography (0-20%MeOH/CH₂Cl₂) to provide11-(benzyloxy)-8-hydroxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dioneas a mixture of diastereomers. MS (m/z) 367.27 [M+H]⁺.

Step 2. Synthesis of11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(9b)

To a solution11-(benzyloxy)-8-hydroxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.057 g, 0.155 mmol) in anhydrous methanol (1 mL) was added 77% m-CPBA(0.139 g, 0.620 mmol) and N-iodosuccinimide (0.140 g, 0.620 mmol). Thereaction mixture was heated at 80° C. for 1 h and cooled to roomtemperature. The solution was diluted with CH₂Cl₂ and washed with 10%aqueous Na₂SO₃ solution. The aqueous phase was extracted with CH₂Cl₂ andthe combined organic phase was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by column chromatography (0-10%MeOH/CH₂Cl₂) to provide11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione.MS (m/z) 493.11 [M+H]⁺.

Step 3. Synthesis of11-(benzyloxy)-8-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(9c)

To a solution of11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.052 g, 0.105 mmol) in DMSO (2 mL) was added2,4,6-trifluorobenzylamine (0.084 g, 0.524 mmol), i-Pr₂NEt (0.091 mL,0.524 mmol), and Pd(PPh₃)₄ (0.006 g, 0.005 mmol). The reaction flask wasevacuated and backfilled with CO (g) three times, then heated to 80° C.for 4 h under 1 atm of CO (g). After cooling to rt, the reaction wasdiluted with EtOAc and washed with 0.05 N HCl (1×), saturated aqueousNaHCO₃ (1×), and brine (1×). The organic phase was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography (0-100% EtOAc/heptane) to provide11-(benzyloxy)-8-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide.MS (m/z) 554.21 [M+H]⁺.

Step 4. Synthesis of(6aS,8R)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(9-1),(6aR,8R)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(9-2),(6aS,8S)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(9-3),(6aR,8S)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(9-4)

11-(benzyloxy)-8-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamidewas separated into its individual stereoisomers by preparative SFC on anAD-H column using 50% i-PrOH (containing 0.1% NH₃) co-solvent to providefour separate peaks sequentially numbered as peak 1 through 4 accordingto order of eluting. Among them, peaks 1 and 4 are enantiomers; peak 2and 3 are enantiomers. Absolute configurations are not confirmed.

The separated stereoisomers were each dissolved in 1:1 toluene/TFA (2mL). The reaction mixture was allowed to stir at rt for 2 h andconcentrated. The residue was dissolved in MeCN and purified bypreparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2 mm)eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30minutes. The combined fractions were lyophilized to afford the titlecompounds. Absolute configurations are not confirmed.

Peak 1: MS (m/z) 464.25 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.52 (t,J=5.7 Hz, 1H), 7.23 (t, J=8.6 Hz, 2H), 6.85 (s, 1H), 5.60 (dd, J=9.4,7.0 Hz, 1H), 4.66 (dd, J=14.6, 5.9 Hz, 1H), 4.55 (dd, J=14.5, 5.5 Hz,1H), 4.16 (dt, J=13.8, 7.3 Hz, 1H), 3.83 (s, 2H), 3.09-3.00 (m, 1H),2.61 (dd, J=12.2, 7.1 Hz, 1H), 2.02-1.90 (m, 2H), 1.88-1.76 (m, 3H),1.70-1.55 (m, 1H), 1.21-1.07 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−108.99 (td, J=9.3, 4.4 Hz), −112.44 (t, J=7.2 Hz).

Peak 2: MS (m/z) 464.26 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (t,J=5.7 Hz, 1H), 7.32-7.16 (m, 2H), 5.68 (d, J=6.7 Hz, 1H), 4.62 (dd,J=14.5, 5.8 Hz, 1H), 4.54 (dd, J=14.6, 5.6 Hz, 1H), 4.18 (dt, J=14.3,7.4 Hz, 1H), 3.81 (d, J=14.2 Hz, 1H), 3.65 (d, J=14.1 Hz, 1H), 3.03 (dt,J=12.1, 5.7 Hz, 1H), 2.25 (dd, J=13.5, 6.9 Hz, 1H), 2.21-2.07 (m, 2H),2.04 (d, J=13.4 Hz, 1H), 1.89-1.76 (m, 2H), 1.73-1.59 (m, 1H), 1.30-1.14(m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.24 (ddd, J=15.5, 9.2, 6.2Hz), −112.44 (t, J=7.2 Hz).

Peak 3: MS (m/z) 464.26 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (t,J=5.7 Hz, 1H), 7.32-7.13 (m, 2H), 5.68 (d, J=6.7 Hz, 1H), 4.62 (dd,J=14.5, 5.8 Hz, 1H), 4.54 (dd, J=14.5, 5.6 Hz, 1H), 4.18 (dt, J=14.1,7.4 Hz, 1H), 3.81 (d, J=14.2 Hz, 1H), 3.65 (d, J=14.1 Hz, 1H), 3.03 (dt,J=12.3, 5.5 Hz, 1H), 2.25 (dd, J=13.4, 6.8 Hz, 1H), 2.21-2.07 (m, 2H),2.04 (d, J=13.4 Hz, 1H), 1.90-1.76 (m, 2H), 1.73-1.59 (m, 1H), 1.31-1.13(m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.24 (ddd, J=15.6, 9.5, 6.3Hz), −112.44 (t, J=7.1 Hz).

Peak 4: MS (m/z) 464.22 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.52 (t,J=5.6 Hz, 1H), 7.23 (t, J=8.7 Hz, 2H), 6.86 (s, 1H), 5.61 (dd, J=9.4,7.1 Hz, 1H), 4.66 (dd, J=14.5, 6.0 Hz, 1H), 4.56 (dd, J=14.7, 5.5 Hz,1H), 4.17 (dt, J=14.5, 7.6 Hz, 1H), 3.84 (s, 2H), 3.06 (dt, J=12.5, 5.7Hz, 1H), 2.62 (dd, J=12.2, 7.0 Hz, 1H), 2.03-1.90 (m, 2H), 1.87-1.78 (m,3H), 1.69-1.55 (m, 1H), 1.23-1.08 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−108.87-−109.12 (m), −112.44 (t, J=7.3 Hz).

Example 10: Preparation of(6aS,8R)—N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(10-1),(6aR,8R)—N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(10-2),(6aS,8S)—N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(10-3), and(6aR,8S)—N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(10-4)

Step 1. Synthesis of11-(benzyloxy)-N-(2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(10a)

To a solution of11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.091 g, 0.185 mmol), prepared according to the preparation ofintermediate 9b in Example 9, in DMSO (3.7 mL) was added2,4-difluorobenzylamine (0.149 g, 1.04 mmol), i-Pr₂NEt (0.161 mL, 0.924mmol), and Pd(PPh₃)₄ (0.011 g, 0.009 mmol). The reaction flask wasevacuated and backfilled with CO (g) three times, then heated to 80° C.for 4 h under 1 atm of CO (g). After cooling to rt, the reaction wasdiluted with EtOAc and washed with 0.05 N HCl (x), saturated aqueousNaHCO₃ (x), and brine (1×). The organic phase was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography (0-100% EtOAc/heptane) to provide11-(benzyloxy)-N-(2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide.MS (m/z) 536.16 [M+H]⁺.

Step 2. Synthesis of (6aS,8R)—N-(2.4difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(10-1), (6aR,8R)—N-(2.4difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(10-2),(6aS,8S)—N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(10-3), and(6aR,8S)—N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(10-4)

11-(benzyloxy)-N-(2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamidewas separated into its individual stereoisomers by preparative SFC on anAD-H column using 50% i-PrOH (containing 0.1% NH₃) co-solvent to providefour separate peaks sequentially numbered as peak 1 through 4 accordingto order of eluting. Among them, peaks 1 and 4 are enantiomers; peak 2and 3 are enantiomers. Absolute configurations are assigned notconfirmed.

The separated stereoisomers were each dissolved in 1:1 toluene/TFA (2mL). The reaction mixture was allowed to stir at rt for 2 h andconcentrated. The residue was dissolved in MeCN and purified bypreparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2 mm)eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30minutes. The combined fractions were lyophilized to afford the titlecompounds. Absolute configurations are assigned not confirmed.

Peak 1: MS (m/z) 446.23 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.44 (t,J=5.8 Hz, 1H), 7.45 (td, J=8.6, 6.6 Hz, 1H), 7.33-7.19 (m, 1H), 7.09(td, J=8.6, 2.6 Hz, 1H), 5.61 (dd, J=9.4, 7.1 Hz, 1H), 4.60 (qd, J=15.0,5.7 Hz, 2H), 4.18 (dt, J=14.1, 7.4 Hz, 1H), 3.85 (s, 2H), 3.07 (dt,J=12.5, 5.7 Hz, 1H), 2.63 (dd, J=12.2, 7.0 Hz, 1H), 2.04-1.92 (m, 2H),1.89-1.77 (m, 3H), 1.71-1.55 (m, 1H), 1.22-1.08 (m, 1H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −112.03 (p, J=8.1 Hz), −114.77 (q, J=8.9 Hz).

Peak 2: MS (m/z) 446.27 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (t,J=5.8 Hz, 1H), 7.44 (td, J=8.7, 6.6 Hz, 1H), 7.26 (ddd, J=10.6, 9.3, 2.6Hz, 1H), 7.08 (td, J=8.5, 2.6 Hz, 1H), 5.68 (d, J=6.7 Hz, 1H), 4.63-4.52(m, 2H), 4.19 (dt, J=13.2, 7.5 Hz, 1H), 3.83 (d, J=14.2 Hz, 1H), 3.68(dd, J=14.1, 1.4 Hz, 1H), 3.05 (ddd, J=13.3, 6.6, 4.7 Hz, 1H), 2.28 (dd,J=13.5, 6.9 Hz, 1H), 2.20 (dd, J=15.5, 6.4 Hz, 1H), 2.15-2.08 (m, 1H),2.06 (d, J=13.5 Hz, 1H), 1.91-1.77 (m, 2H), 1.73-1.62 (m, 1H), 1.30-1.16(m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −112.32 (p, J=7.7 Hz), −114.96 (q,J=8.8 Hz).

Peak 3: MS (m/z) 446.26 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (t,J=5.9 Hz, 1H), 7.50-7.37 (m, 1H), 7.26 (td, J=10.0, 2.6 Hz, 1H), 7.08(td, J=8.5, 2.5 Hz, 1H), 5.68 (d, J=6.8 Hz, 1H), 4.64-4.51 (m, 2H), 4.19(dt, J=14.1, 7.5 Hz, 1H), 3.83 (d, J=14.2 Hz, 1H), 3.68 (d, J=14.1 Hz,1H), 3.05 (dt, J=12.3, 5.5 Hz, 1H), 2.28 (dd, J=13.5, 6.8 Hz, 1H), 2.20(dd, J=15.4, 6.4 Hz, 1H), 2.16-2.09 (m, 1H), 2.06 (d, J=13.4 Hz, 1H),1.92-1.78 (m, 2H), 1.74-1.62 (m, 1H), 1.30-1.15 (m, 1H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −112.32 (p, J=7.6 Hz), −114.96 (q, J=8.5 Hz).

Peak 4: MS (m/z) 446.24 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (t,J=5.8 Hz, 1H), 7.44 (td, J=8.7, 6.6 Hz, 1H), 7.26 (td, J=9.9, 2.6 Hz,1H), 7.08 (td, J=8.5, 2.7 Hz, 1H), 5.61 (dd, J=9.4, 7.1 Hz, 1H), 4.59(qd, J=14.9, 5.8 Hz, 2H), 4.17 (dt, J=14.2, 7.4 Hz, 1H), 3.84 (s, 2H),3.05 (dd, J=12.8, 5.9 Hz, 1H), 2.62 (dd, J=12.2, 7.1 Hz, 1H), 2.03-1.92(m, 2H), 1.89-1.76 (m, 3H), 1.69-1.57 (m, 1H), 1.22-1.08 (m, 1H). ¹⁹FNMR (376 MHz, DMSO-d₆) δ −112.03 (p, J=8.2 Hz), −114.77 (q, J=8.9 Hz).

Example 11: Preparation of(6aR,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(11-1),(6aS,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(11-2),(6aR,7R,8R)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(11-3), and(6aS,7R,8R)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(11-4)

Step 1. Synthesis of tert-butyl3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)-1.2dihydroxyethyl)-3-((tert-butoxycarbonyl)amino)azepane-1-carboxylate(11a)

To a solution of tert-butyl(E)-3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)vinyl)-3-((tert-butoxycarbonyl)amino)azepane-1-carboxylate(0.595 g, 0.994 mmol), prepared according to the preparation ofintermediate 1d in Example 1, in 1:1 acetone/water (14.3 mL) was addedNMO (0.233 g, 1.99 mmol) and 2.5% OSO₄ solution in tBuOH (0.125 mL,0.010 mmol). The reaction mixture was stirred at rt for 24 h, quenchedwith saturated aqueous sodium thiosulfate and NaHCO₃, and stirred 1 h.The mixture was concentrated and CH₂Cl₂ was added. The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (2×). Thecombined organic phase was dried over Na₂SO₄, filtered, concentrated,and purified by column chromatography (0-80% EtOAc/hexanes) to providetert-butyl3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)-1,2-dihydroxyethyl)-3-((tert-butoxycarbonyl)amino)azepane-1-carboxylate.MS (m/z) 632.87 [M+H]⁺.

Step 2. Synthesis of11-(benzyloxy)-7,8-dihydroxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(11b)

To a solution of tert-butyl3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)-1,2-dihydroxyethyl)-3-((tert-butoxycarbonyl)amino)azepane-1-carboxylate(0.519 g, 0.821 mmol) in CH₂Cl₂ (20 mL) at 0° C. was addedtrifluoroacetic acid (4.00 mL, 50.5 mmol). The reaction mixture wasstirred for 2 h, warmed to rt, concentrated, and dried under high vacuumfor 1 h. The residue was dissolved in ethanol (20 mL) and heated at 90°C. for 3 h. The reaction mixture was cooled to rt, concentrated, andpurified by column chromatography to provide11-(benzyloxy)-7,8-dihydroxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione.MS (m/z) 383.26 [M+H]⁺.

Step 3. Synthesis of11-(benzyloxy)-7,8-dihydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(11c)

To a solution11-(benzyloxy)-7,8-dihydroxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.100 g, 0.261 mmol) in anhydrous methanol (2 mL) was added 77% m-CPBA(0.234 g, 1.05 mmol) and N-iodosuccinimide (0.235 g, 1.05 mmol). Thereaction mixture was heated at 80° C. for 0.5 h and cooled to roomtemperature. The solution was diluted with CH₂Cl₂ and washed with 10%aqueous Na₂SO₃ solution. The aqueous phase was extracted with CH₂Cl₂ andthe combined organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography (0-10% MeOH/CH₂Cl₂) to provide11-(benzyloxy)-7,8-dihydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione.MS (m/z) 509.09 [M+H]⁺.

Step 4. Synthesis of11-(benzyloxy)-7,8-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(11d)

To a solution of11-(benzyloxy)-7,8-dihydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.027 g, 0.053 mmol) in DMSO (2 mL) was added2,4,6-trifluorobenzylamine (0.043 g, 0.266 mmol), i-Pr₂NEt (0.046 mL,0.266 mmol), and Pd(PPh₃)₄ (0.003 g, 0.003 mmol). The reaction flask wasevacuated and backfilled with CO (g) three times, then heated to 80° C.for 4 h under 1 atm of CO (g). After cooling to rt, the reaction wasdiluted with EtOAc and washed with 0.05 N HCl (1×), saturated aqueousNaHCO₃ (1×), and brine (1×). The organic phase was dried over Na₂SO₄,filtered, concentrated, and purified by column chromatography (0-20%MeOH/CH₂Cl₂) to provide11-(benzyloxy)-7,8-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide.MS (m/z) 570.21 [M+H]⁺.

Step 5. Synthesis of(6aR,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(11-1),(6aS,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(11-2),(6aR,7R,8R)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(11-3), and(6aS,7R,8R)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(11-4)

11-(benzyloxy)-7,8-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamidewas separated into its individual stereoisomers by preparative SFC on anIB column using 40% MeOH co-solvent to provide four separate peakssequentially numbered as peak 1 through 4 according to order of eluting.Among them, peaks 1 and 4 are enantiomers; peak 2 and 3 are enantiomers.Absolute configurations are assigned not confirmed.

The separated stereoisomers were each dissolved in 1:1 toluene/TFA (2mL). The reaction mixture was allowed to stir at rt for 2 h andconcentrated. The residue was dissolved in MeCN and purified bypreparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2 mm)eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30minutes. The combined fractions were lyophilized to afford the titlecompounds. Absolute configurations are assigned not confirmed.

Peak 1: MS (m/z) 480.20 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (t,J=5.7 Hz, 1H), 7.22 (t, J=8.6 Hz, 2H), 5.74 (s, 1H), 5.53 (s, 1H), 4.57(qd, J=14.6, 5.7 Hz, 2H), 4.20 (dt, J=13.7, 6.9 Hz, 1H), 4.06 (s, 1H),3.79 (d, J=14.6 Hz, 1H), 3.65 (d, J=14.6 Hz, 1H), 3.03 (dt, J=12.6, 6.0Hz, 1H), 2.49-2.43 (m, 1H), 2.17-2.06 (m, 1H), 2.00 (dd, J=15.5, 7.1 Hz,1H), 1.86-1.75 (m, 2H), 1.78-1.59 (m, 1H), 1.25 (d, J=15.5 Hz, 1H). ¹⁹FNMR (376 MHz, DMSO-d₆) δ −109.28 (ddd, J=15.6, 9.3, 6.2 Hz), −112.43 (t,J=7.2 Hz).

Peak 2: MS (m/z) 480.21 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.50 (t,J=5.7 Hz, 1H), 7.23 (t, J=8.6 Hz, 2H), 6.98 (s, 1H), 5.10 (d, J=8.0 Hz,1H), 4.65 (dd, J=14.6, 5.8 Hz, 1H), 4.55 (dd, J=14.6, 5.4 Hz, 1H), 4.15(dt, J=13.5, 6.9 Hz, 1H), 4.06 (d, J=7.9 Hz, 1H), 3.83-3.70 (m, 2H),3.05 (dt, J=12.8, 6.0 Hz, 1H), 2.32-2.25 (m, 1H), 1.86-1.74 (m, 2H),1.75-1.69 (m, 1H), 1.69-1.59 (m, 1H), 1.50 (dd, J=15.1, 7.2 Hz, 1H),1.34-1.26 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −108.87-−109.08 (m),−112.43 (t, J=7.4 Hz).

Peak 3: MS (m/z) 480.22 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.51 (t,J=5.7 Hz, 1H), 7.28-7.18 (m, 2H), 6.99 (s, 1H), 5.10 (d, J=8.0 Hz, 1H),4.66 (dd, J=14.7, 5.8 Hz, 1H), 4.56 (dd, J=14.6, 5.5 Hz, 1H), 4.21-4.11(m, 1H), 4.07 (d, J=8.2 Hz, 1H), 3.81-3.72 (m, 2H), 3.10-3.02 (m, 1H),2.33-2.25 (m, 1H), 1.88-1.70 (m, 3H), 1.70-1.59 (m, 1H), 1.51 (dd,J=14.6, 7.5 Hz, 1H), 1.32-1.24 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−108.87-−109.07 (m), −112.43 (t, J=7.2 Hz).

Peak 4: MS (m/z) 480.20 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (t,J=5.7 Hz, 1H), 7.28-7.13 (m, 2H), 5.74 (s, 1H), 5.53 (s, 1H), 4.57 (qd,J=14.5, 5.7 Hz, 2H), 4.20 (dt, J=13.4, 6.8 Hz, 1H), 4.06 (s, 1H), 3.79(d, J=14.5 Hz, 1H), 3.65 (d, J=14.6 Hz, 1H), 3.03 (dt, J=13.0, 6.1 Hz,1H), 2.17-2.06 (m, 1H), 2.00 (dd, J=15.4, 7.3 Hz, 1H), 1.85-1.74 (m,2H), 1.74-1.61 (m, 1H), 1.35-1.24 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−109.28 (ddd, J=9.4, 6.5, 3.0 Hz), −112.43 (t, J=7.1 Hz).

Example 12: Preparation of(6aS,8R)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(12-1),(6aR,8S)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(12-2),(6aS,8S)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(12-3), and(6aR,8R)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(12-4)

Step 1. Synthesis of11-(benzyloxy)-9-iodo-8-methoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(12a)

To a solution of11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.035 g, 0.071 mmol), prepared according to the preparation ofintermediate 9b in Example 9, in DMF (1 mL) at rt was added 60% sodiumhydride (0.004 g, 0.107 mmol). After 5 min, iodomethane (0.009 mL, 0.142mmol) was added. The reaction was stirred for 2 h, quenched with MeOH,concentrated, and purified by column chromatography (0-10% MeOH/CH₂Cl₂).The impure residue was purified again by column chromatography (20-100%EtOAc/hexanes) to provide11-(benzyloxy)-9-iodo-8-methoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione.MS (m/z) 507.10 [M+H]⁺.

Step 2. Synthesis of11-(benzyloxy)-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(12b)

To a solution of11-(benzyloxy)-9-iodo-8-methoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.016 g, 0.032 mmol) in DMSO (1 mL) was added2,4,6-trifluorobenzylamine (0.026 g, 0.160 mmol), i-Pr₂NEt (0.028 mL,0.160 mmol), and Pd(PPh₃)₄ (0.002 g, 0.002 mmol). The reaction flask wasevacuated and backfilled with CO (g) three times, then heated to 80° C.for 4 h under 1 atm of CO (g). After cooling to rt, the reaction wasdiluted with EtOAc and washed with 0.05 N HCl (1×), saturated aqueousNaHCO₃ (1×), and brine (1×). The organic phase was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography (0-10% MeOH/CH₂Cl₂) to provide11-(benzyloxy)-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamideas two separable stereoisomers.

Peak 1 (major): MS (m/z) 568.15 [M+H]⁺.

Peak 2 (minor): MS (m/z) 568.18 [M+H]⁺.

Step 3. Synthesis of(6aS,8R)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(12-1),(6aR,8S)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(12-2),(6aS,8S)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(12-3), and(6aR,8R)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(12-4)

The major diastereomer of11-(benzyloxy)-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(Peak 1 from 12b) was separated into its individual stereoisomers bypreparative SFC on an AD-H column using 40% MeOH co-solvent to providetwo separate peaks. The separated stereoisomers were each dissolved in1:1 toluene/TFA (2 mL). The reaction mixture was allowed to stir at rtfor 2 h and concentrated. The residue was dissolved in MeCN and purifiedby preparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2 mm)eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30minutes. The combined fractions were lyophilized to afford the titlecompounds. Absolute configurations are assigned not confirmed.

Peak 1: MS (m/z) 478.19 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (t,J=5.6 Hz, 1H), 7.32-7.13 (m, 2H), 5.68 (d, J=5.6 Hz, 1H), 4.63 (dd,J=14.4, 6.1 Hz, 1H), 4.47 (dd, J=14.4, 5.1 Hz, 1H), 4.18 (dt, J=13.6,7.1 Hz, 1H), 3.81 (d, J=14.2 Hz, 1H), 3.63 (d, J=14.3 Hz, 1H), 3.39 (s,3H), 3.02 (dt, J=12.7, 5.7 Hz, 1H), 2.27 (d, J=13.5 Hz, 1H), 2.13-2.02(m, 3H), 1.87-1.76 (m, 2H), 1.72-1.61 (m, 1H), 1.31-1.24 (m, 1H). ¹⁹FNMR (376 MHz, DMSO-d₆) δ −109.34 (tt, J=9.7, 6.4 Hz), −112.45 (t, J=7.3Hz).

Peak 2: MS (m/z) 478.18 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (t,J=5.6 Hz, 1H), 7.26-7.16 (m, 2H), 5.68 (d, J=5.6 Hz, 1H), 4.63 (dd,J=14.5, 6.0 Hz, 1H), 4.47 (dd, J=14.5, 5.2 Hz, 1H), 4.18 (dt, J=13.8,7.1 Hz, 1H), 3.81 (d, J=14.2 Hz, 1H), 3.63 (d, J=14.3 Hz, 1H), 3.39 (s,3H), 3.02 (dt, J=12.5, 5.7 Hz, 1H), 2.27 (d, J=13.5 Hz, 1H), 2.13-2.03(m, 3H), 1.86-1.76 (m, 2H), 1.71-1.62 (m, 1H), 1.31-1.24 (m, 1H). ¹⁹FNMR (376 MHz, DMSO-d₆) δ −109.34 (ddd, J=9.0, 6.4, 2.9 Hz), −112.45 (t,J=7.2 Hz).

The minor diastereomer of11-(benzyloxy)-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(Peak 2 from 12b) was separated into its individual stereoisomers bypreparative SFC on an OJ-H column using 20% EtOH co-solvent to providetwo separate peaks. The separated stereoisomers were each dissolved in1:1 toluene/TFA (2 mL). The reaction mixture was allowed to stir at rtfor 2 h and concentrated. The residue was dissolved in MeCN and purifiedby preparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2 mm)eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30minutes. The combined fractions were lyophilized to afford the titlecompounds. Absolute configurations are assigned not confirmed.

Peak 1: MS (m/z) 478.12 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (t,J=5.6 Hz, 1H), 7.22-7.14 (m, 2H), 5.37 (t, J=7.6 Hz, 1H), 4.55 (dd,J=14.3, 6.2 Hz, 1H), 4.41 (dd, J=14.5, 5.1 Hz, 1H), 4.16 (dt, J=14.2,7.6 Hz, 1H), 3.85-3.74 (m, 2H), 3.27 (s, 3H), 3.09-3.00 (m, 1H), 2.76(dd, J=12.4, 7.2 Hz, 1H), 1.89-1.72 (m, 5H), 1.67-1.56 (m, 1H),1.16-1.05 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.64 (ddd, J=9.4,6.4, 3.0 Hz), −112.09 (t, J=7.1 Hz).

Peak 2: MS (m/z) 478.13 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.67 (t,J=5.6 Hz, 1H), 7.25-7.17 (m, 2H), 5.37 (t, J=7.6 Hz, 1H), 4.56 (dd,J=14.2, 6.1 Hz, 1H), 4.42 (dd, J=14.4, 5.0 Hz, 1H), 4.17 (dt, J=14.0,7.6 Hz, 1H), 3.87-3.74 (m, 2H), 3.28 (s, 3H), 3.09-3.01 (m, 1H), 2.77(dd, J=12.3, 7.2 Hz, 1H), 1.94-1.75 (m, 5H), 1.69-1.52 (m, 1H),1.21-1.00 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.64 (tt, J=9.0, 6.1Hz), −112.09 (t, J=7.2 Hz).

Example 13: Preparation of(6aR,7S,8S)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(13-1),(6aS,7R,8R)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(13-2),(6aR,7R,8R)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(13-3), and(6aS,7S,8S)-11-hydroxy-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(13-4)

Step 1. Synthesis of11-(benzyloxy)-7,8-dimethoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(13a)

To a solution of11-(benzyloxy)-7,8-dihydroxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.250 g, 0.654 mmol), prepared according to the preparation ofintermediate 11b in Example 11, in DMF (20 mL) at rt was added 60%sodium hydride (0.063 g, 1.63 mmol). After 5 min, iodomethane (0.163 mL,2.61 mmol) was added. The reaction was stirred for 2 h, quenched withMeOH, concentrated, and purified by column chromatography (0-100%EtOAc/heptane then 0-10% MeOH/CH₂Cl₂) to provide11-(benzyloxy)-7,8-dimethoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione.MS (m/z) 411.28 [M+H]⁺.

Step 2. Synthesis of 11-(benzyloxy)-9-iodo-7.8dimethoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(13b)

To a solution11-(benzyloxy)-7,8-dimethoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.036 g, 0.088 mmol) in anhydrous methanol (1 mL) was added 77% m-CPBA(0.079 g, 0.351 mmol) and N-iodosuccinimide (0.079 g, 0.351 mmol). Thereaction mixture was heated at 80° C. for 1 h and cooled to roomtemperature. The solution was diluted with CH₂Cl₂ and washed with 10%aqueous Na₂SO₃ solution. The aqueous phase was extracted with CH₂Cl₂ andthe combined organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography (0-10% MeOH/CH₂Cl₂) to provide11-(benzyloxy)-9-iodo-7,8-dimethoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione.MS (m/z) 537.08 [M+H]⁺.

Step 3. Synthesis of 11-(benzyloxy-7.8dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(13c)

To a solution of11-(benzyloxy)-9-iodo-7,8-dimethoxy-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.034 g, 0.064 mmol) in DMSO (1.4 mL) was added2,4,6-trifluorobenzylamine (0.052 g, 0.322 mmol), i-Pr₂NEt (0.056 mL,0.322 mmol), and Pd(PPh₃)₄ (0.004 g, 0.003 mmol). The reaction flask wasevacuated and backfilled with CO (g) three times, then heated to 80° C.for 4 h under 1 atm of CO (g). After cooling to rt, the reaction wasdiluted with EtOAc and washed with 0.05 N HCl (1×), saturated aqueousNaHCO₃ (1×), and brine (1×). The organic phase was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography (0-100% EtOAc/heptane) to provide11-(benzyloxy)-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide.MS (m/z) 598.15 [M+H]⁺.

Step 4. Synthesis of (6aR,7S,8S)-11-hydroxy-7.8dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(13-1), (6aS,7R,8R)-11-hydroxy-7.8dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(13-2), (6aR,7R,8R)-11-hydroxy-7.8dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(13-3), and (6aS,7S,8S)-11-hydroxy-7.8dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(13-4)

11-(benzyloxy)-7,8-dimethoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamidewas separated into its individual stereoisomers by preparative SFC on anIA column using 50% i-PrOH (containing 0.1% NH₃) co-solvent to providefour separate peaks, sequentially numbered as peak 1 through 4 accordingto order of eluting. The separated stereoisomers were each dissolved in1:1 toluene/TFA (2 mL). The reaction mixture was allowed to stir at rtfor 2 h and concentrated. The residue was dissolved in MeCN and purifiedby preparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2 mm)eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30minutes. The combined fractions were lyophilized to afford the titlecompounds. Absolute configurations are assigned not confirmed.

Peak 1: MS (m/z) 508.22 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (t,J=5.6 Hz, 1H), 7.32-7.13 (m, 2H), 5.76 (s, 1H), 5.52 (s, 1H), 4.61 (dd,J=14.5, 5.9 Hz, 1H), 4.51 (dd, J=14.5, 5.4 Hz, 1H), 4.20 (dt, J=13.0,6.3 Hz, 1H), 4.05 (s, 1H), 3.79 (s, 2H), 3.53 (s, 3H), 3.40 (s, 3H),3.04 (dt, J=12.8, 5.8 Hz, 1H), 2.21-2.07 (m, 1H), 1.94-1.73 (m, 4H),1.42-1.22 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.24 (tt, J=9.4, 6.3Hz), −112.28-−112.58 (m).

Peak 2: MS (m/z) 508.24 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (t,J=5.6 Hz, 1H), 7.23 (t, J=8.6 Hz, 2H), 5.76 (s, 1H), 5.52 (s, 1H), 4.61(dd, J=14.5, 5.9 Hz, 1H), 4.51 (dd, J=14.5, 5.4 Hz, 1H), 4.26-4.15 (m,1H), 4.05 (s, 1H), 3.79 (s, 2H), 3.53 (s, 3H), 3.40 (s, 3H), 3.04 (dt,J=12.7, 5.9 Hz, 1H), 2.15 (dd, J=15.5, 10.0 Hz, 1H), 1.92-1.75 (m, 4H),1.40-1.25 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.24 (tt, J=9.4, 6.3Hz), −112.45 (t, J=7.3 Hz).

Peak 3: MS (m/z) 508.20 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (t,J=5.6 Hz, 1H), 7.26-7.09 (m, 2H), 4.89 (d, J=7.4 Hz, 1H), 4.46 (qd,J=14.4, 5.5 Hz, 2H), 4.14 (dt, J=14.3, 7.4 Hz, 1H), 4.02-3.81 (m, 3H),3.48 (s, 3H), 3.39 (s, 3H), 3.09-3.00 (m, 1H), 2.15-1.99 (m, 1H),1.89-1.76 (m, 2H), 1.75-1.61 (m, 1H), 1.54 (dd, J=15.3, 6.5 Hz, 1H),1.26-1.09 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.66 (tt, J=9.5, 6.2Hz), −112.01 (t, J=7.0 Hz).

Peak 4: MS (m/z) 508.21 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (t,J=5.6 Hz, 1H), 7.31-7.09 (m, 2H), 4.90 (d, J=7.3 Hz, 1H), 4.47 (qd,J=14.4, 5.7 Hz, 2H), 4.15 (dt, J=14.1, 7.4 Hz, 1H), 3.98-3.82 (m, 3H),3.48 (s, 3H), 3.40 (s, 3H), 3.10-3.02 (m, 1H), 2.13-2.02 (m, 1H),1.89-1.78 (m, 2H), 1.75-1.64 (m, 1H), 1.54 (dd, J=15.2, 6.6 Hz, 1H),1.28-1.12 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.66 (tt, J=9.1, 6.3Hz), −112.01 (t, J=7.1 Hz).

Example 14: Preparation of(6aR,8R)—N-(3-chloro-2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(14-1) and(6aR,8S)—N-(3-chloro-2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(14-2)

Synthesis of (6aR)-11-(benzyloxy)-N-(3-chloro-2.4difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide

To a solution of(6aR)-11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(0.261 g, 0.530 mmol) (intermediate 9b), in DMSO (10 mL) was added3-chloro-2,4-difluorobenzylamine (0.471 g, 2.65 mmol), i-Pr₂NEt (0.462mL, 2.65 mmol), and Pd(PPh₃)₄ (0.031 g, 0.026 mmol). The reaction flaskwas evacuated and backfilled with CO (g) three times, then heated to 80°C. for 4 h under 1 atm of CO (g). After cooling to rt, the reaction wasdiluted with EtOAc and washed with 0.05 N HCl (1×), saturated aqueousNaHCO₃ (1×), and brine (1×). The organic phase was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography (0-100% EtOAc/heptane) to provide(6aR)-11-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide.MS (m/z) 570.15 [M+H]⁺.

Synthesis of (6aR,8R)—N-(3-chloro-2.4difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(14-1) and (6aR,8S)—N-(3-chloro-2.4difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(14-2)

(6aR)-11-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamidewas separated into its individual stereoisomers by preparative SFC on anIB column using 45% methanol co-solvent to provide two separate peaks.The separated stereoisomers were each dissolved in 1:1 toluene/TFA (10mL for Peak 1; 6 mL for Peak 2). The reaction mixture was allowed tostir at rt for 2 h and concentrated. The residue was dissolved in MeCNand purified by preparative HPLC (column, Gemini 10μ C18 110A, AXI/;250×21.2 mm) eluting 5-100/0 acetonitrile (0.1% TFA) in water (0.1% TFA)over 30 minutes. The combined fractions were lyophilized to afford thetitle compounds.

Peak 1 (14-1): MS (m/z) 480.31 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.84(t, J=5.9 Hz, 1H), 7.42 (td, J=8.5, 6.2 Hz, 1H), 7.31 (td, J=8.8, 1.7Hz, 1H), 5.67 (dd, J=6.7, 3.5 Hz, 1H), 5.34 (d, J=3.4 Hz, 1H), 4.68-4.54(m, 2H), 4.18 (dt, J=13.0, 7.5 Hz, 1H), 3.82 (d, J=14.2 Hz, 1H), 3.67(d, J=13.9 Hz, 1H), 3.05 (ddd, J=13.2, 6.5, 4.6 Hz, 1H), 2.27 (dd,J=13.4, 6.8 Hz, 1H), 2.19 (dd, J=15.5, 6.4 Hz, 1H), 2.14-2.00 (m, 2H),1.92-1.77 (m, 2H), 1.74-1.59 (m, 1H), 1.30-1.14 (m, 1H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −116.15 (td, J=7.4, 6.1, 2.2 Hz), −118.37 (d, J=8.2 Hz).

Peak 2 (14-2): MS (m/z) 480.21 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.45(t, J=5.9 Hz, 1H), 7.43 (td, J=8.4, 6.2 Hz, 1H), 7.31 (td, J=8.8, 1.7Hz, 1H), 5.60 (dd, J=9.4, 7.0 Hz, 1H), 4.64 (qd, J=15.1, 5.9 Hz, 2H),4.17 (dt, J=13.2, 7.4 Hz, 1H), 3.84 (s, 2H), 3.06 (dt, J=13.2, 5.7 Hz,1H), 2.62 (dd, J=12.2, 7.1 Hz, 1H), 2.02-1.90 (m, 2H), 1.90-1.76 (m,3H), 1.70-1.56 (m, 1H), 1.23-1.08 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−115.86 (ddd, J=8.7, 6.1, 2.4 Hz), −118.16 (d, J=8.0 Hz).

Example 15: Preparation of(6aS,8S)-8,11-dihydroxy-8-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(15)

Step 1. Resolution of tert-butyl(R)-3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate (15a-1)and tert-butyl(S)-3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate (15a-2)

Racemictert-butyl-3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylatewas resolved using chiral SFC (15% ACN) to give tert-butyl(R)-3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate (15a-1)and tert-butyl(S)-3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate(15a-2).

Step 2. Synthesis of(6aS)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (15b)

The title compound was synthesized in a similar manner to11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(1f), using tert-butyl(R)-3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate (15a-1)in place of tert-butyl3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate (1c).

Step 3. Synthesis of(6aS)-11-(benzyloxy-3,4,5,6-tetrahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,8,10(7H)-trione(15c)

To a solution of(6aS)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (15b, 2.0 g, 5.7 mmol) in THF (100 mL)was added LiHMDS (1.0M in THF, 17.1 mL) dropwise at −78° C., and theresulting dark solution was stirred for 30 min. Oz (g) was bubbledthrough the reaction, which was warmed to rt, while bubbling O₂ (g)through the reaction for 20 min. The reaction was quenched with MeOH,concentrated, and purified via combiflash (24 g, MeOH/DCM) to give thetitle product.

Step 4. Synthesis of(6aS,8S)-11-(benzyloxy)-8-hydroxy-8-methyl-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(15d)

MeLi (3.1M in diethoxymethane, 0.32 mL) followed by MeMgBr (3.0M in THF,0.165 mL) was added to THF (6 mL) at −78° C., and the resulting solutionwas stirred for 1 hour. A solution of(6aS)-11-(benzyloxy)-3,4,5,6-tetrahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,8,10(7H)-trione(15c, 120 mg, 0.33 mmol) in THF (6 mL) was added dropwise, and thesolution was stirred at −78° C. for 1 hr. The reaction was quenched withwater, filtered, and filter cake washed sequentially with DCM and MeOH.The filtrate was concentrated, dissolved in DMF/TFA, and purified byGilson HPLC (0-100% ACN/H₂O) to give the title product as a singlestereoisomer, assigned tentatively.

Step 5. Synthesis of(6aS,8S)-11-(benzyloxy)-8-hydroxy-8-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(15e)

The title compound was prepared in a similar manner to11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1g) using(6aS,8S)-11-(benzyloxy)-8-hydroxy-8-methyl-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(15d) in place of11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(1f). The reaction was purified using Gilson HPLC (5-100% ACN/H₂O+0.1%TFA) to give the title compound.

Step 6. Synthesis of(6aS,8S)-8,11-dihydroxy-8-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(15)

TFA (1 mL) was added to a solution of(6aS,8S)-11-(benzyloxy)-8-hydroxy-8-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(15e, 38 mg, 0.0067 mmol) in toluene (1 mL) and the resulting solutionwas stirred for 3 hr. The reaction was concentrated, dissolved in DMF,and purified by Gilson HPLC (0-100% ACN/H2O) to give the title product.1H NMR (400 MHz, DMSO-d6) δ 11.68 (t, J=5.5 Hz, 1H), 7.73 (s, 1H),7.35-7.16 (m, 2H), 4.81-4.38 (m, 2H), 4.24-4.12 (m, 1H), 3.86 (d, J=14.4Hz, 1H), 3.74 (d, J=14.4 Hz, 1H), 3.00 (dt, J=13.3, 6.7 Hz, 1H),2.41-2.36 (m, 1H), 2.26-2.13 (m, 2H), 1.89-1.71 (m, 5H), 1.69 (s, 3H);MS (m/z) 478.2 [M+H]⁺.

Example 16: Preparation of(6aS)-11-hydroxy-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide:(16)

Step 1. Synthesis of(6aS)-11-(benzyloxy)-8-(hydroxymethyl)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(16a)

To a solution of(6aS)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (15b, 100 mg, 0.43 mmol) in THF (4 mL)at −78° C., was added LDA (1.0M in THF/Hexanes, 0.86 mL), and theresulting solution was stirred for 10 min. A solution of1H-benzotriazole-1-methanol in THF (2 mL) was added, and the solutionwas stirred at −78° C. for 1 hour. Reaction was quenched with MeOH,concentrated, and purified via combiflash (12 g, MeOH/DCM) to givedesired product as a mixture of diastereomers.

Step 2. Synthesis of(6aS,8S)-11-(benzyloxy)-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(16b-1) and(6aS,8R)-11-(benzyloxy-(hydroxymethyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(16b-2)

The title compounds were prepared in a similar manner to11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(1g) using(6aS)-11-(benzyloxy)-8-(hydroxymethyl)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(16a) in place of11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(1f). The mixture was purified using Gilson HPLC (5-100% ACN/H₂O+0.1%TFA) to give the title compounds as separated diastereomers.

Step 3. Synthesis of(6aS)-11-hydroxy-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(16)

To a solution of(6aS)-11-(benzyloxy)-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(16b-2, peak 2) in toluene (0.5 mL) was added TFA (0.5 mL), and theresulting solution was stirred for 3 hours. The reaction wasconcentrated, redissolved in 1:1 THF/MeOH (1 mL) and LiOH (2M in H2O,0.05 mL) was added. The solution was stirred for 1.5 hrs, and 0.15 mL INHCl was added. The reaction was concentrated, redissolved in DMF, andpurified by Gilson HPLC (5-100% ACN/H₂O) to give the title compound. 1HNMR (400 MHz, Chloroform-d) δ 11.09 (s, 1H), 6.78-6.57 (m, 2H),4.75-4.56 (m, 3H), 4.47 (dt, J=13.7, 6.9 Hz, 1H), 4.09 (dd, J=10.8, 6.4Hz, 1H), 3.90 (dd, J=10.7, 6.3 Hz, 1H), 3.73-3.52 (m, 2H), 3.02 (dt,J=12.9, 6.1 Hz, 1H), 2.47-1.94 (m, 5H), 1.86 (dt, J=14.7, 7.4 Hz, 1H),1.83-1.70 (m, 1H), 1.58 (dd, J=15.8, 7.8 Hz, 1H); MS (m/z) 478.2 [M+H]⁺.

Example 17: Preparation of(6aR,8R)-8,11-dihydroxy-8-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(17)

The title compound was prepared in a similar manner to(6aS,8S)-8,11-dihydroxy-8-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide (15), using tert-butyl(S)-3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate (15a-2)in place of(R)-3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate(15a-1), stereochemistry tentatively assigned. 1H NMR (400 MHz, DMSO-d6)δ 11.68 (t, J=5.5 Hz, 1H), 7.73 (s, 1H), 7.35-7.16 (m, 2H), 4.81-4.38(m, 2H), 4.24-4.12 (m, 1H), 3.86 (d, J=14.4 Hz, 1H), 3.74 (d, J=14.4 Hz,1H), 3.00 (dt, J=13.3, 6.7 Hz, 1H), 2.41-2.36 (m, 1H), 2.26-2.13 (m,2H), 1.89-1.71 (m, 5H), 1.69 (s, 3H); MS (m/z) 478.1 [M+H]⁺.

Example 18: Preparation of(6aR)-11-hydroxy-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(18)

Step 1. Synthesis of(6aR)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (18a)

The title compound was synthesized in a similar manner to11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione(1f), using tert-butyl(S)-3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate (15a-2)in place of tert-butyl3-((tert-butoxycarbonyl)amino)-3-formylazepane-1-carboxylate (1c).

Step 2. Synthesis of(6aR)-11-hydroxy-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(18)

The title compound was prepared in a similar to(6aS)-11-hydroxy-8-(hydroxymethyl)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(16), using(6aR)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (18a) in place of(6aS)-11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-1,10-dione (15b). 1H NMR (400 MHz, Methanol-d4) δ6.96-6.86 (m, 2H), 4.72-4.56 (m, 2H), 4.37 (dt, J=14.6, 7.8 Hz, 1H),4.26 (tt, J=8.3, 3.8 Hz, 1H), 4.00-3.90 (m, 1H), 3.87 (d, J=18.4 Hz,1H), 3.83-3.72 (m, 1H), 3.25-3.11 (m, 1H), 2.37 (dd, J=13.0, 8.3 Hz,1H), 2.26 (dd, J=13.0, 8.8 Hz, 1H), 2.07-1.87 (m, 4H), 1.78 (d, J=14.7Hz, 1H), 1.32 (dq, J=15.7, 7.7 Hz, 1H); MS (m/z) 478.1 [M+H]⁺.

Example 19: Preparation of(1R,11S,14S)—N-[(2,4-difluorophenyl)methyl]-3,7-dihydroxy-14-methoxy-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide(19-1, 19-2, and 19-3)

Step 1: synthesis of methyl(3S,7S)-3-amino-7-methyl-1,2,4,7-tetrahydroazepine-3-carboxylate bis TFASalt

O1-benzyl O3-methyl(3S,7S)-3-(benzyloxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dicarboxylate(5 g, 11.0 mmol) was heated in TFA (25 mL) at 100° C. for 4 hours.

The reaction was cooled to Mt concentrated, the resulting residue wascoevaporated with EtOAc (8×20 mL) and used directly in next step.LCMS-ESI+ (m/z): calcd H+ for C9H16N2O2, Theoretical: 184.12, Found:185.02.

Step 2: Synthesis of O1-tert-butyl O3-methyl(3S,7S)-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dicarboxylate

Methyl (3S,7S)-3-amino-7-methyl-1,2,4,7-tetrahydroazepine-3-carboxylatebis TFA salt (4.556 g, 11.1 mol) was dissolved in EtOAc (84.0 mL) atroom temperature. Saturated aqueous sodium carbonate solution (13.2 mL)was added followed by Di-tert-butyl dicarbonate (7.235 g, 33.2 mmol).The resulting mixture was heated to 70° C. for overnight. The reactionwas cooled to room temperature, diluted with EtOAc, washed with water,brine, dried over sodium sulfate, filtered and concentrated, purified bynormal phase chromatography. LCMS-ESI+ (m/z): calcd H+ for C19H32N2O6,Theoretical: 384.23, Found: 384.746.

Step 3: Synthesis of tert-butyl(3S,7S)-3-(tert-butoxycarbonylamino)-3-(hydroxymethyl)-7-methyl-4.7dihydro-2H-azepine-1-carboxylate

O1-tert-butyl O3-methyl(3S,7S)-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dicarboxylate(3.756 g, 9.77 mmol) was dissolved in THF (97.0 mL) and cooled to 0° C.The resulting mixture was flushed with nitrogen before 1.0 M LAH in THF(12.7 mL, 12.7 mmol) was added. The reaction was stirred at 0° C. for 10minutes and then was removed from cooling bath and stirred at roomtemperature for 30 minutes. The reaction was cooled back to 0° C. andquenched with saturated Rochelle's salt dropwise. The mixture was thendiluted with EtOAc, organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated and used directly in nextstep. LCMS-ESI+ (m/z): calcd H+ for C18H32N2O5, Theoretical: 356.23,Found: 356.837.

Step 4: Synthesis of tert-butyl(3S,7S)-3-(tert-butoxycarbonylamino)-3-formyl-7-methyl-4.7dihydro-2H-azepine-1-carboxylate

tert-Butyl(3S,7S)-3-(tert-butoxycarbonylamino)-3-(hydroxymethyl)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate(3.48 g, 9.76 mmol) was dissolved in DCM (65 mL) and cooled to 0° C.Dess-Martin periodinane (6.21 g, 14.6 mmol) was added in portions. Thereaction was warmed up to room temperature after addition and stirredfor overnight. The reaction was cooled back to 0° C., 1 N sodiumthiosulfate (80 mL) was added, saturated sodium bicarbonate (80 mL) wasadded. The mixture was stirred vigorously for 30 minutes. Layers wereseparated, aqueous layer was extracted with DCM (×2). Combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated. The resulting product was purified by normal phasechromatography (80 g silica gel 0-40% EtOAc/Hexane). LCMS-ESI+ (m/z):calcd H+ for C18H30N2O5, Theoretical: 354.22, Found: 355.016.

Step 5: Synthesis of tert-butyl(3R,7S)-3-[(E)-2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)vinyl]-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate

Methyl3-benzyloxy-6-(dimethoxyphosphorylmethyl)-4-oxo-pyran-2-carboxylate(1.96 g, 5.12 mmol) was dissolved in THF (25 mL) and cooled to −78° C.1.0M LDA in THF/Hexane (5.12 mL, 5.12 mmol) was added dropwise. Theresulting mixture was stirred at −78° C. for 45 minutes. After that, asolution of tert-butyl(3S,7S)-3-(tert-butoxycarbonylamino)-3-formyl-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate(1.21 g, 3.4 mmol) in THF (9 mL) was added into the cold mixture. Thenewly formed mixture was stirred at −78° C. for 10 minutes and thenwarmed up to −10° C. in one hour and stirred at −10° C. for another 60minutes. The reaction was quenched with saturated ammonium chlorideslowly. The mixture was diluted with EtOAc, washed with saturatedammonium chloride, brine, dried over sodium sulfate, filtered andconcentrated and purified by normal phase chromatography. LCMS-ESI+(m/z): calcd H+ for C33H42N2O9, Theoretical: 610.29, Found: 610.897.

Step 6: Synthesis of tert-butyl(3S,7S)-3-[2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)ethyl]-3-(tert-butoxycarbonylamino)-7-methyl-4.7dihydro-2H-azepine-1-carboxylate

The solution of tert-butyl(3R,7S)-3-[(E)-2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)vinyl]-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate(650 mg, 1.06 mmol) in Toluene (32.5 mL) was purged with nitrogen.Poly(methylhydrosiloxane) (0.64 g, 10.6 mmol) was added under nitrogenfollowed bychloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I) (78mg, 0.16 mmol) and 2.0M sodium tert-butoxide in THF (0.16 mL, 0.319mmol). The reaction was then stirred under nitrogen balloon for 1 hour.The reaction was quenched with water, stirred vigorously for 30 minutes,brine (20 mL) was added, stirred for another 10 minutes, extracted withEtOAc. The organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated. Purified by normal phasechromatography. LCMS-ESI+ (m/z): calcd H+ for C33H44N2O9, Theoretical:612.30, Found: 612.746.

Step 7: Synthesis of(1S,11S)-7-benzyloxy-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-6,9-dione

tert-Butyl(3S,7S)-3-[2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)ethyl]-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate(0.41 g, 0.669 mmol) was dissolved in DCM (16 mL) and cooled to 0° C.,TFA was added slowly dropwise along the side of the flask. The newlyformed mixture was stirred at 0° C. for 30 minutes and then at roomtemperature for 2 hours. The reaction was concentrated, coevaporatedwith DCM (3×5 mL), further dried over the vacuum line for 3 hours. Thenthe residue was dissolved in EtOH (40 mL) and heated to 90° C. for 2hours. The reaction was cooled to room temperature, concentrated,purified by normal phase chromatography. LCMS-ESI+ (m/z): calcd H+ forC22H22N2O3, Theoretical: 362.16, Found: 363.30.

Step 8: Synthesis of(1S,11S-7-benzyloxy-5-iodo-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-6,9-dione

To a solution of(1S,11S)-7-benzyloxy-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-6,9-dione(640 mg, 1.77 mmol) in MeOH (34 mL) at room temperature was added MCPBA(792 mg, 3.53 mmol) and NIS (795 mg, 3.53 mmol). The resulting mixturewas heated to 80° C. for 20 minutes. The reaction was cooled to roomtemperature, diluted with DCM, washed with 1 N sodium thiosulfate,saturated NaHCO₃, dried over sodium sulfate, filtered and concentratedand purified by normal phase chromatography. LCMS-ESI+ (m/z): calcd H+for C22H21N2O3, Theoretical: 488.06, Found: 489.139.

Step 9: Synthesis of (1S,11S)-7-benzyloxy-N-[(2.4difluorophenyl)methyl]-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide

To the solution of(1S,11S)-7-benzyloxy-5-iodo-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-6,9-dione(285 mg, 0.584 mmol) in DMSO (12 mL) at room temperature was added(2,4-difluorophenyl)methanamine (418 mg, 2.92 mmol) followed by DIPEA(377 mg, 2.92 mmol), Tetrakis(triphenylphosphine)palladium(0) (33.7 mg,0.0292 mmol) and PdCl₂dppf (21.4 mg, 0.0292 mmol). The resulting mixturewas degassed and flushed with CO three times and then under CO balloon,heated to 85° C. for 3 hours. The reaction was cooled to roomtemperature, diluted with EtOAc, washed with water, saturated NH₄Cl,brine, dried over sodium sulfate, filtered and concentrated and purifiedby normal phase chromatography. LCMS-ESI+ (m/z): calcd H+ forC30H27F2N3O4, Theoretical: 531.20, Found: 532.203.

Step 10: Synthesis of (1R,1S)-7-benzyloxy-N-[(2.4difluorophenyl)methyl]-11-methyl-6,9,14-trioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide

(1S,11S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide(210 mg, 0,395 mmol) was dissolved in 1,4-dioxane (4 mL). Seleniumdioxide (263 mg, 2.37 mmol) was added. The resulting mixture was heatedat 100° C. for 6 hours. The reaction was cooled to room temperature,filtered through Celite, concentrated and purified by normal phasechromatography. LCMS-ESI+ (m/z): calcd H+ for C30H25F2N3O5, Theoretical:545.18, Found: 546.174.

Step 11: Synthesis of (1R,11S,14S)-7-benzyloxy-N-[(2.4difluorophenyl)methyl]-14-hydroxy-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide

The solution of(1R,11S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-11-methyl-6,9,14-trioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide(189 mg, 0.346 mmol) in MeOH (5 mL) was cooled to 0° C., CeCl3·7H2O (129mg, 0.346 mmol) was added followed by sodium borohydride (15.27 mg, 0.4mmol). The reaction was stirred for 5 minutes before it was quenchedwith water. The reaction was extracted with DCM, the organic layer waswashed with brine, dried over sodium sulfate, filtered and concentratedand purified by normal phase chromatography. LCMS-ESI+ (m/z): calcd H+for C30H27F2N3O5, Theoretical: 547.19, Found: 548.124.

Step 12: Synthesis of (1R,11S,14S)-7-benzyloxy-N-[(2.4difluorophenyl)methyl]-14-methoxy-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide

The solution of(1R,11S,14S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-hydroxy-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide(100 mg, 0.183 mmol) in DMF (3.6 mL) was cooled to 0° C., NaH (60%dispersion in mineral oil) (9.5 mg, 0.237 mmol) was added, the newlyformed mixture was stirred for 10 minutes before a solution ofIodomethane (28.5 mg, 0.20 mmol) in DMF (1 mL) was added dropwise. Afterstirred for 10 minutes at 0° C., the reaction was quenched withsaturated NH4Cl, extracted with EtOAc, the organic layer was washed withwater, brine, dried over sodium sulfate, filtered and concentrated andpurified by normal phase chromatography. Stereochemistry at C4 positionis not confirmed. LCMS-ESI+ (m/z): calcd H+ for C31H29F2N3O5,Theoretical: 561.21, Found: 562.149.

Step 13: Synthesis of (1R,11S,14S)—N-[(2.4difluorophenyl)methyl]-7-hydroxy-14-methoxy-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4.7diene-5-carboxamide (19-1)

To the solution of(1R,11S,14S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-methoxy-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide(13.5 mg, 0.024 mmol) in EtOH (10 mL) was added 20% Pd(OH)2/C (50 wt %water) (3.0 mg), the resulting mixture was degassed and flushed withnitrogen three times, then it was degassed and flushed with hydrogenthree times before it was hydrogenated under hydrogen balloon for 4hours at room temperature. The reaction was degassed and flushed withnitrogen, filtered through 0.45 um syringe filter, concentrated,redissolved in DMF, filtered and purified by reverse phase prep HPLC.LCMS-ESI+ (m/z): calcd H+ for C24H25F2N3O5, Theoretical: 473.18, Found:474.263. 1H NMR (400 MHz, Acetone-d6) δ 10.88 (s, 1H), 7.53-7.43 (m,1H), 7.08-6.94 (m, 2H), 4.62 (pd, J=15.2, 6.1 Hz, 3H), 3.96-3.82 (m,2H), 3.63-3.57 (m, 1H), 3.57-3.51 (m, 1H), 3.45 (s, 3H), 3.43-3.32 (m,2H), 2.92-2.88 (m, 1H), 2.16 (dd, J=16.1, 3.4 Hz, 1H), 2.00-1.81 (m,3H), 1.28 (d, J=6.7 Hz, 3H), 1.24-1.16 (m, 1H).

Step 14: Synthesis of (1R,11S,14S)—N-[(2.4difluorophenyl)methyl]-7-hydroxy-14-methoxy-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide(19-2)

(1R,11S,14S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-methoxy-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide(6 mg, 0.0107 mmol) was treated with a 1:1 mixture of Toluene/TFA (3.0mL) at room temperature overnight. The reaction was concentrated,redissolved in DMF, filtered and purified by reverse phase prep HPLC.LCMS-ESI+ (m/z): calcd H+ for C24H23F2N3O5, Theoretical: 471.16, Found:472.203. 1H NMR (400 MHz, Chloroform-d) δ 10.79 (s, 1H), 7.39 (td,J=8.7, 6.5 Hz, 1H), 6.92-6.76 (m, 2H), 5.66 (dt, J=11.6, 3.2 Hz, 1H),5.52 (ddd, J=11.5, 2.6, 1.6 Hz, 1H), 5.36 (dq, J=7.2, 2.6 Hz, 2H), 4.65(s, 2H), 4.28 (q, J=3.0 Hz, 1H), 4.07-3.92 (m, 2H), 3.63 (ddd, J=18.7,10.1, 8.4 Hz, 1H), 3.38 (d, J=13.7 Hz, 1H), 3.28 (s, 3H), 2.72 (dd,J=12.8, 8.3 Hz, 1H), 1.78 (dt, J=12.7, 9.7 Hz, 1H), 1.38 (d, J=7.3 Hz,3H).

Step 15: Synthesis of (1R,11S,14S)-7-benzyloxy-N-[(2.4difluorophenyl)methyl]-3-hydroxy-14-methoxy-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide

The solution of(1R,11S,14S)-7-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-methoxy-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide(41.8 mg, 0.0744 mmol) in THF (2 mL) was cooled to −78° C., 1.0 M LHMDSin THF (0.373 mL, 0.373 mmol) was added. The resulting mixture wasstirred for 25 minutes and then a solution of2-(benzenesulfonyl)-3-phenyl-oxaziridine (77.8 mg, 0.298 mmol) in THF(0.8 mL) was added to the cold mixture dropwise. After stirred at −78°C. for 30 minutes, the reaction was warmed up to −10° C. and stirred atthat temperature for 90 minutes. The reaction was quenched with MeOH,concentrated, purified by normal phase chromatography. LCMS-ESI+(m/z):calcd H+ for C31H29F2N3O6, Theoretical: 577.20, Found: 578.211.

Step 16: Synthesis of (1R,11S,14S)—N-[(2.4 difluorophenyl)methyl]-3.7dihydroxy-14-methoxy-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide(19-3)

The residue from previous step was dissolved in toluene (0.3 mL), cooledto 0° C., TFA (0.3 mL) was added. The reaction was slowly warmed up toroom temperature as ice melted and stirred at room temperature forovernight. The reaction was concentrated, redissolved in DMF, filteredand purified by reverse phase prep HPLC. LCMS-ESI+ (m/z): calcd H+ forC24H23F2N3O6, Theoretical: 487.16, Found: 488.255. 1H NMR (400 MHz,Chloroform-d) δ 11.14 (s, 1H), 7.46-7.33 (m, 1H), 6.93-6.79 (m, 2H),5.73 (t, J=7.7 Hz, 1H), 5.67 (dt, J=11.5, 3.2 Hz, 1H), 5.53 (ddd,J=11.5, 2.6, 1.6 Hz, 1H), 5.42-5.32 (m, 1H), 4.68 (d, J=5.5 Hz, 2H),4.13 (q, J=3.0 Hz, 1H), 4.05 (d, J=13.8 Hz, 1H), 3.55 (d, J=13.8 Hz,1H), 3.25 (s, 4H), 3.18-3.08 (m, 2H), 1.90 (dd, J=12.8, 7.9 Hz, 1H),1.40 (d, J=7.2 Hz, 3H).

Intermediate 20a

Step 1: synthesis of methyl(3S,7S)-3-amino-7-methyl-1,2,4,7-tetrahydroazepine-3-carboxylate bis TFASalt

O1-benzyl O3-methyl(3S,7S)-3-(benzyloxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dicarboxylate(5 g, 11.0 mmol) was heated in TFA (25 mL) at 100° C. for 4 hours. Thereaction was cooled to rt, concentrated, the resulting residue wascoevaporated with EtOAc (8×20 mL) and used directly in next step.LCMS-ESI+ (m/z): calcd H+ for C9H16N2O2, Theoretical: 184.12, Found:185.02. Methyl(3S,7S)-3-amino-7-methyl-1,2,4,7-tetrahydroazepine-3-carboxylate bis TFAsalt (4.556 g, 11.1 mol) was dissolved in EtOAc (84.0 mL) at roomtemperature. Saturated aqueous sodium carbonate solution (13.2 mL) wasadded followed by Di-tert-butyl dicarbonate (7.235 g, 33.2 mmol). Theresulting mixture was heated to 70° C. for overnight. The reaction wascooled to room temperature, diluted with EtOAc, washed with water,brine, dried over sodium sulfate, filtered and concentrated, purified bynormal phase chromatography. LCMS-ESI+ (m/z): calcd H+ for C19H32N2O6,Theoretical: 384.23, Found: 384.746.

Step 2: Synthesis of tert-butyl(3S,7S)-3-(tert-butoxycarbonylamino)-3-(hydroxymethyl)-7-methyl-4.7dihydro-2H-azepine-1-carboxylate

O1-tert-butyl O3-methyl(3S,7S)-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dicarboxylate(3.756 g, 9.77 mmol) was dissolved in THF (97.0 mL) and cooled to 0° C.The resulting mixture was flushed with nitrogen before 1.0M LAH in THF(12.7 mL, 12.7 mmol) was added. The reaction was stirred at 0° C. for 10minutes and then was removed from cooling bath and stirred at roomtemperature for 30 minutes. The reaction was cooled back to 0° C. andquenched with saturated Rochelle's salt dropwise. The mixture was thendiluted with EtOAc, organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated and used directly in nextstep. LCMS-ESI+ (m/z): calcd H+ for C18H32N2O5, Theoretical: 356.23,Found: 356.837.

Step 3: Synthesis of tert-butyl(3S,7S)-3-(tert-butoxycarbonylamino)-3-formyl-7-methyl-4.7dihydro-2H-azepine-1-carboxylate

tert-butyl(3S,7S)-3-(tert-butoxycarbonylamino)-3-(hydroxymethyl)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate(3.48 g, 9.76 mmol) was dissolved in DCM (65 mL) and cooled to 0° C.Dess-Martin periodinane (6.21 g, 14.6 mmol) was added in portions. Thereaction was warmed up to room temperature after addition and stirredfor overnight. The reaction was cooled back to 0° C., IN sodiumthiosulfate (80 mL) was added, saturated sodium bicarbonate (80 mL) wasadded. The mixture was stirred vigorously for 30 minutes. Layers wereseparated, aqueous layer was extracted with DCM (×2). Combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated. The resulting product was purified by normal phasechromatography (80 g silica gel 0-40% EtOAc/Hexane). LCMS-ESI+ (m/z):calcd H+ for C18H30N2O5, Theoretical: 354.22, Found: 355.016.

Step 4: Synthesis of tert-butyl(3R,7S)-3-[(E)-2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)vinyl]-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate

Methyl3-benzyloxy-6-(dimethoxyphosphorylmethyl)-4-oxo-pyran-2-carboxylate(1.96 g, 5.12 mmol) was dissolved in THF (25 mL) and cooled to −78° C.1.0M LDA in THF/Hexane (5.12 mL, 5.12 mmol) was added dropwise. Theresulting mixture was stirred at −78° C. for 45 minutes. After that, asolution of tert-butyl(3S,7S)-3-(tert-butoxycarbonylamino)-3-formyl-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate(1.21 g, 3.4 mmol) in THF (9 mL) was added into the cold mixture. Thenewly formed mixture was stirred at −78° C. for 10 minutes and thenwarmed up to −10° C. in one hour and stirred at −10° C. for another 60minutes. The reaction was quenched with saturated ammonium chlorideslowly. The mixture was diluted with EtOAc, washed with saturatedammonium chloride, brine, dried over sodium sulfate, filtered andconcentrated and purified by normal phase chromatography. LCMS-ESI+(m/z): calcd H+ for C33H42N2O9, Theoretical: 610.29, Found: 610.897.

Step 5: Synthesis of tert-butyl(3S,7S)-3-[2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)ethyl]-3-(tert-butoxycarbonylamino)-7-methyl-4.7dihydro-2H-azepine-1-carboxylate

The solution of tert-butyl(3R,7S)-3-[(E)-2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)vinyl]-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate(650 mg, 1.06 mmol) in Toluene (32.5 mL) was purged with nitrogen.poly(methylhydrosiloxane) (0.64 g, 10.6 mmol) was added under nitrogenfollowed byChloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I) (78mg, 0.16 mmol) and 2.0M Sodium tert-butoxide in THF (0.16 mL, 0.319mmol). The reaction was then stirred under nitrogen balloon for 1 hour.The reaction was quenched with water, stirred vigorously for 30 minutes,brine (20 mL) was added, stirred for another 10 minutes, extracted withEtOAc. The organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated. Purified by normal phasechromatography. LCMS-ESI+ (m/z): calcd H+ for C33H44N2O9, Theoretical:612.30, Found: 612.746.

Step 6: Synthesis of(1S,11S)-7-benzyloxy-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-6,9-dione

tert-butyl(3S,7S)-3-[2-(5-benzyloxy-6-methoxycarbonyl-4-oxo-pyran-2-yl)ethyl]-3-(tert-butoxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1-carboxylate(0.41 g, 0.669 mmol) was dissolved in DCM (16 mL) and cooled to 0° C.,TFA was added slowly dropwise along the side of the flask. The newlyformed mixture was stirred at 0° C. for 30 minutes and then at roomtemperature for 2 hours. The reaction was concentrated, coevaporatedwith DCM (3×5 mL), further dried over the vacuum line for 3 hours. Thenthe residue was dissolved in EtOH (40 mL) and heated to 90° C. for 2hours. The reaction was cooled to room temperature, concentrated,purified by normal phase chromatography. LCMS-ESI+ (m/z): calcd H+ forC22H22N2O3, Theoretical: 362.16, Found: 363.30.

Intermediate 20b

Step 1: Synthesis of(1S,11S)-7-benzyloxy-5-iodo-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-6,9-dione

To a solution of(1S,11S)-7-benzyloxy-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-6,9-dione(640 mg, 1.77 mmol) in MeOH (34 mL) at room temperature was added MCPBA(792 mg, 3.53 mmol) and NIS (795 mg, 3.53 mmol). The resulting mixturewas heated to 80° C. for 20 minutes. The reaction was cooled to roomtemperature, diluted with DCM, washed with 1N sodium thiosulfate,saturated NaHCO3, dried over sodium sulfate, filtered and concentratedand purified by normal phase chromatography. 1H NMR (400 MHz,Chloroform-d) δ 7.68-7.57 (m, 2H), 7.39-7.26 (m, 3H), 5.64-5.51 (m, 2H),5.51-5.39 (m, 2H), 5.15 (d, J=10.1 Hz, 1H), 3.74 (d, J=13.6 Hz, 1H),3.30-3.19 (m, 3H), 2.59-2.49 (m, 2H), 2.25-2.09 (m, 2H), 1.23 (d, J=5.8Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C22H21IN2O3: 489.07, found:489.1.

Step 2: Synthesis of (1S,11S)-7-benzyloxy-N-[(2.4difluorophenyl)methyl]-11-methyl-6,9-dioxo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-5-carboxamide

To the solution of(1S,11S)-7-benzyloxy-5-iodo-11-methyl-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadeca-4,7,12-triene-6,9-dione(285 mg, 0.584 mmol) in DMSO (12 mL) at room temperature was added(2,4-difluorophenyl)methanamine (418 mg, 2.92 mmol) followed by DIPEA(377 mg, 2.92 mmol), Tetrakis(triphenylphosphine)palladium(0) (33.7 mg,0.0292 mmol) and PdCl2dppf (21.4 mg, 0.0292 mmol). The resulting mixturewas degassed and flushed with CO three times and then under CO balloon,heated to 85° C. for 3 hours. The reaction was cooled to roomtemperature, diluted with EtOAc, washed with water, saturated NH4Cl,brine, dried over sodium sulfate, filtered and concentrated and purifiedby normal phase chromatography to give Intermediate 20b. LCMS-ESI+(m/z): [M+H]+ calcd for C30H27F2N3O4, Theoretical: 531.20, Found:532.203.

Intermediate 20c

Intermediate 20c was prepared in a manner similar to that ofIntermediate 20b. 1H NMR (400 MHz, Chloroform-d) δ 10.83 (t, J=5.7 Hz,1H), 7.61-7.49 (m, 2H), 7.39-7.27 (m, 3H), 6.72-6.59 (m, 2H), 5.59 (ddd,J=13.0, 7.3, 3.8 Hz, 1H), 5.50-5.40 (m, 3H), 5.19 (d, J=10.3 Hz, 1H),4.64 (d, J=5.6 Hz, 2H), 4.10 (dd, J=18.5, 8.4 Hz, 1H), 3.81 (d, J=13.6Hz, 1H), 3.49 (ddd, J=19.0, 11.7, 7.9 Hz, 1H), 3.07 (d, J=13.6 Hz, 1H),2.52 (d, J=7.5 Hz, 2H), 2.22 (dd, J=12.8, 7.8 Hz, 1H), 1.93 (td, J=12.2,8.8 Hz, 1H), 1.28 (d, J=7.2 Hz, 3H). LCMS-ESI+(m/z): [M+H]+ calcd forC30H26F3N3O4: 550.19, found: 550.2.

Example 20: Preparation of(3S,6aS)-11-hydroxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,6,7,8,10-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(20)

To Intermediate 20c (20 mg) was added toluene (0.75 mL) then TFA (0.75mL). The reaction was stirred under ambient atmosphere at 20° C., withmonitoring by LCMS, until all starting material was consumed. Thereaction was diluted with acetonitrile and concentrated in vacuo.Purification by silica gel flash column chromatography (0 to 20%methanol in dichloromethane) yielded compound 20. 1H NMR (400 MHz,Chloroform-d) δ 10.59 (t, J=5.8 Hz, 1H), 6.68 (dd, J=8.7, 7.5 Hz, 2H),5.62 (ddt, J=8.1, 4.4, 2.0 Hz, 1H), 5.58-5.48 (m, 1H), 5.48-5.36 (m,1H), 4.66 (d, J=5.6 Hz, 2H), 4.17 (dd, J=19.1, 9.2 Hz, 1H), 3.97 (d,J=13.6 Hz, 1H), 3.51 (ddd, J=18.9, 11.2, 7.9 Hz, 1H), 3.34 (d, J=13.6Hz, 1H), 2.57 (dd, J=16.5, 8.3 Hz, 1H), 2.56-2.45 (m, 1H), 2.30 (dd,J=12.8, 7.8 Hz, 1H), 2.10-1.97 (m, 1H), 1.37 (d, J=7.3 Hz, 3H).LCMS-ESI+ (m/z): [M+H]+ calcd for C23H20F3N3O4: 460.1, found: 460.2.

Example 21: Preparation of(3S,6aR,8R)-8,11-dihydroxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,6,7,8,10-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamideand(3S,6aR,8S)-8,11-dihydroxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,6,7,8,10-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(21-1 and 21-2)

Step 1. To 20a (25 mg) was added THF (0.7 mL). The reaction flask wascooled to −80° C., then LiHMDS (1 M in THF, 50 uL) was added dropwise.After 5 min at −80° C.,(rac)-3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (36 mg, 2 equiv) wasadded as solution in THF (1 mL). The reaction was stirred at −80° C.After 30 min, more LiHMDS (1 M in THF, 30 uL), then more Davisoxaziridine (36 mg) in THF (1 mL) were added. The reaction was allowedto slowly warm over 60 min to −10° C., then it was quenched by additionof methanol. The mixture was removed from cooling bath and concentratedin vacuo. Purification by silica gel flash column chromatography (0 to20% MeOH in DCM) yielded the desired product as a mixture ofdiastereomers. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H22N2O4: 379.17,found: 379.3.

Step 2. To the product from Step 1 (28 mg) was added mCPBA (66 mg, 4equiv), then NIS (66 mg, 4 equiv), then MeOH (3 mL). Vial was sealedunder ambient atmosphere and stirred in metal heating block at 80° C.After 1 hr, the reaction was allowed to cool to 20° C. The reaction wasdiluted with DCM, then washed with 1 N aq sodium thiosulfate, then oncewith satd aq NaHCO3. The combined aqueous phases were extracted withDCM. The combined organic phases were dried over MgSO₄, filtered, andconcentrated in vacuo. Purification by silica gel flash columnchromatography (0 to 20% MeOH in DCM) yielded the desired product.LCMS-ESI+ (m/z): [M+H]+ calcd for C22H21IN2O4: 505.06, found: 505.1.

Step 3. To the product from Step 2 (35 mg) under argon in DMSO (1.5 mL)was added 2,4,6-trifluorobenzylamine (56 mg, 5 equiv) then DIPEA (60 μL,5 equiv). The flask was cycled five times between high vacuum and COatmosphere. Then Pd(PPh₃)₄ (4 mg, 0.05 equiv) was added. The flask wasagain cycled five times between high vacuum and CO atmosphere, then thereaction was warmed to 85° C. in metal heating block for 2 hr, at whichpoint all starting material was consumed by LCMS. The reaction wasallowed to cool to 20° C. Diluted with ethyl acetate. The organic phasewas washed with 0.2 N HCl (2×), then water (2×), then brine (1×). Theorganic phase was dried over MgSO₄, filtered, and concentrated in vacuo.Purification by silica gel flash column chromatography (25 to 100% ethylacetate in hexane) yielded the desired product as a mixture ofdiastereomers. Further purification by chiral SFC (Daicel Chiralpak AD-Hcolumn, 50% iPrOH in CO2 with NH3 modifier) yielded two diastereomers.Peak 1 (earlier-eluting product, structure tentatively assigned): H NMR(400 MHz, Chloroform-d) δ 10.78 (t, J=5.6 Hz, 1H), 7.59-7.53 (m, 2H),7.37-7.29 (m, 3H), 6.68 (dd, J=8.7, 7.5 Hz, 2H), 5.69 (d, J=7.2 Hz, 1H),5.66-5.57 (m, 1H), 5.49 (d, J=10.3 Hz, 1H), 5.48-5.42 (m, 2H), 5.18 (d,J=10.3 Hz, 1H), 4.70 (dd, J=14.5, 5.9 Hz, 1H), 4.62 (dd, J=14.5, 5.5 Hz,1H), 3.82 (d, J=13.6 Hz, 1H), 3.05 (d, J=13.6 Hz, 1H), 2.90 (dd, J=16.6,8.9 Hz, 1H), 2.69 (dq, J=16.7, 3.5 Hz, 1H), 2.37 (d, J=14.0 Hz, 1H),2.10 (dd, J=14.0, 7.4 Hz, 1H), 1.27 (d, J=7.3 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C30H26F3N3O5: 566.19, found: 566.2. Peak 2(later-eluting product, structure tentatively assigned): 1H NMR (400MHz, Chloroform-d) δ 11.42 (t, J=5.6 Hz, 1H), 7.56-7.45 (m, 2H),7.39-7.27 (m, 3H), 7.08 (s, 1H), 6.68 (t, J=8.1 Hz, 2H), 5.70 (dd,J=9.3, 7.4 Hz, 1H), 5.64-5.54 (m, 1H), 5.52-5.38 (m, 3H), 5.23 (d,J=10.5 Hz, 1H), 4.68 (d, J=5.6 Hz, 2H), 3.82 (d, J=13.8 Hz, 1H), 3.14(d, J=13.7 Hz, 1H), 2.71 (dd, J=12.9, 7.3 Hz, 1H), 2.55-2.39 (m, 2H),2.01 (dd, J=12.9, 9.3 Hz, 1H), 1.29 (d, J=7.2 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C30H26F3N3O5: 566.19, found: 566.2.

Step 4. To Peak 1 from Step 3 was added toluene, then TFA. The reactionwas stirred at 20° C., with monitoring by LCMS until starting materialwas consumed. The reaction was diluted with acetonitrile andconcentrated in vacuo. Purification by reverse-phase preparative HPLC(acetonitrile/water, 0.1% TFA modifier) yielded 21-1. 1H NMR (400 MHz,Acetonitrile-d3) δ 10.68 (s, 1H), 6.86 (t, J=8.5 Hz, 2H), 5.62 (d, J=5.3Hz, 2H), 5.49 (d, J=11.4 Hz, 1H), 5.28 (s, 1H), 4.63 (d, J=5.2 Hz, 2H),3.95 (d, J=13.8 Hz, 1H), 3.35 (d, J=13.7 Hz, 1H), 2.81 (dd, J=17.0, 8.7Hz, 1H), 2.65 (d, J=17.0 Hz, 1H), 2.28 (d, J=1.6 Hz, 2H), 1.29 (d, J=6.9Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C23H20F3N3O5: 476.14, found:476.3.

Step 4. To Peak 2 from Step 3 was added toluene, then TFA. The reactionwas stirred at 20° C., with monitoring by LCMS until starting materialwas consumed. The reaction was diluted with acetonitrile andconcentrated in vacuo. Purification by reverse-phase preparative HPLC(acetonitrile/water, 0.1% TFA modifier) yielded 21-2. 1H NMR (400 MHz,Acetonitrile-d3) δ 11.34 (s, 1H), 6.97 (s, 1H), 6.86 (t, J=8.6 Hz, 2H),5.58 (dt, J=8.1, 6.0 Hz, 2H), 5.48 (dt, J=11.7, 2.3 Hz, 1H), 5.27 (s,1H), 4.73-4.53 (m, 2H), 3.96 (d, J=13.9 Hz, 1H), 3.48 (d, J=13.8 Hz,1H), 2.76 (dd, J=12.7, 7.2 Hz, 1H), 2.56 (dd, J=16.8, 8.6 Hz, 1H),2.46-2.34 (m, 1H), 2.02-1.96 (m, 1H), 1.30 (d, J=7.2 Hz, 3H). LCMS-ESI+(m/z): [M+H]+ calcd for C23H20F3N3O5: 476.14, found: 476.2.

Intermediate 22a

To screw-top vial under argon was added 20c (130 mg), then dioxane (4.8mL), then selenium dioxide (210 mg, 8 equiv). The vial was sealed underargon and stirred at 100° C. for 6 hr. The mixture was filtered throughCelite to remove insolubles, washing with ethyl acetate, andconcentrated in vacuo. Purification by silica gel flash columnchromatography (25 to 100% ethyl acetate in hexane) yielded 22a. 1H NMR(400 MHz, Chloroform-d) δ 10.74 (t, J=5.7 Hz, 1H), 7.60-7.49 (m, 2H),7.41-7.26 (m, 3H), 6.67 (dd, J=8.8, 7.5 Hz, 2H), 6.28 (dd, J=11.9, 2.5Hz, 1H), 5.99 (dd, J=11.9, 1.7 Hz, 1H), 5.60 (qt, J=7.5, 2.2 Hz, 1H),5.46 (d, J=10.1 Hz, 1H), 5.08 (d, J=10.2 Hz, 1H), 4.65 (d, J=5.5 Hz,2H), 4.11 (dd, J=18.8, 8.8 Hz, 1H), 3.97 (d, J=14.3 Hz, 1H), 3.81 (ddd,J=18.8, 10.9, 8.5 Hz, 1H), 3.45 (d, J=14.3 Hz, 1H), 2.31 (dd, J=13.3,8.4 Hz, 1H), 2.03-1.93 (m, 1H), 1.39 (d, J=7.4 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₀H₂₆F₃N₃O₅: 564.2, found: 564.1.

Intermediate 22b

To a glass screw-top vial charged with Intermediate 22a (80 mg) wasadded methanol (4 mL), then cerium chloride heptahydrate (69 mg, 1.3equiv), then sodium borohydride (5.5 mg, 1 equiv). The reaction wasstirred at 20° C. for 30 min, quenched with saturated aqueous sodiumbicarbonate, then extracted with 95:5 dichloromethane:methanol. Thecombined organic phases were dried over magnesium sulfate, filtered andconcentrated to yield Intermediate 22b, which was used in subsequentsteps without any further purification. 1H NMR (400 MHz, Chloroform-d) δ10.89-10.77 (m, 1H), 7.60-7.50 (m, 2H), 7.39-7.29 (m, 3H), 6.67 (dd,J=8.7, 7.5 Hz, 2H), 5.56 (dt, J=11.4, 3.2 Hz, 1H), 5.47-5.40 (m, 1H),5.38 (dt, J=7.2, 2.3 Hz, 1H), 5.32-5.26 (m, 1H), 5.19 (d, J=10.4 Hz,1H), 4.96 (s, 1H), 4.74 (dd, J=14.5, 6.6 Hz, 1H), 4.47 (dd, J=14.4, 4.6Hz, 1H), 3.94-3.78 (m, 2H), 3.68-3.54 (m, 1H), 3.05 (d, J=13.8 Hz, 1H),2.72 (dd, J=12.7, 8.4 Hz, 1H), 1.72-1.64 (m, 1H), 1.26 (d, J=7.3 Hz,3H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₀H₂₆F₃N₃O₅: 566.2, found: 566.2.

Example 22: Preparation of(3S,6S,6aR)-11-hydroxy-6-methoxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,6,7,8,10-hexahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(22)

Step 1. To glass vial charged with Intermediate 22b (80 mg) under argonwas added DMF (2.8 mL). The vial was cooled to 0° C., then NaH (60% inmineral oil, 7.4 mg, 1.3 equiv) was added. The reaction was stirred at0° C. for 5 min, then MeI (10 μL, 1.1 equiv). The reaction was stirredat 0° C. for 1 hr. Then the reaction was quenched with saturated aqueousNH4Cl, and extracted into ethyl acetate. The organic phase was washedwith water, then brine. The combined aqueous phases were back-extractedwith more ethyl acetate. The combined organic phases were dried overMgSO₄, filtered, and concentrated in vacuo. Silica gel flash columnchromatography (25 to 100% ethyl acetate in hexane) yielded the desiredproduct. 1H NMR (400 MHz, Chloroform-d) δ 10.87 (s, 1H), 7.62-7.53 (m,2H), 7.35 (dd, J=8.0, 6.1 Hz, 3H), 6.76-6.63 (m, 2H), 5.62 (dt, J=11.4,3.1 Hz, 1H), 5.53 (d, J=10.5 Hz, 1H), 5.50-5.45 (m, 1H), 5.42 (dq,J=7.5, 2.3 Hz, 1H), 5.24 (d, J=10.4 Hz, 1H), 4.67 (d, J=4.2 Hz, 2H),4.26 (d, J=3.2 Hz, 1H), 3.95 (dd, J=18.5, 8.9 Hz, 1H), 3.85 (d, J=13.8Hz, 1H), 3.62 (ddd, J=18.8, 10.7, 8.5 Hz, 1H), 3.28 (s, 3H), 3.05 (d,J=13.7 Hz, 1H), 2.63 (dd, J=12.7, 8.3 Hz, 1H), 1.66 (ddd, J=12.9, 10.8,9.1 Hz, 1H), 1.29 (d, J=7.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC31H28F3N3O5: 580.2, found: 580.2.

Step 2. To the product from Step 1 (5 mg) was added toluene (0.18 mL)then TFA (0.18 mL). The reaction was sealed under ambient atmosphere andstirred at 60° C., with monitoring by LCMS, until all starting materialwas consumed. The reaction was diluted with acetonitrile andconcentrated in vacuo. Purification by silica gel flash columnchromatography (0 to 20% methanol in dichloromethane) yielded compound22. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.61 (s, 1H), 6.85 (t, J=8.5Hz, 2H), 5.63 (dt, J=11.5, 3.2 Hz, 1H), 5.49 (ddd, J=11.6, 2.7, 1.6 Hz,1H), 5.22 (d, J=7.9 Hz, 1H), 4.65-4.50 (m, 2H), 4.26 (q, J=3.0 Hz, 1H),3.97 (d, J=13.9 Hz, 1H), 3.77 (dd, J=18.5, 9.1 Hz, 1H), 3.43 (d, J=9.0Hz, 1H), 3.40-3.32 (m, 1H), 3.21 (s, 3H), 2.53 (dd, J=12.8, 8.2 Hz, 1H),1.85-1.72 (m, 1H), 1.28 (d, J=7.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcdfor C24H22F3N3O5: 490.2, found: 490.2.

Example 23: Preparation of(3S,6S,6aR)-6,11-dihydroxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamideand(3S,6S,6aR)-11-hydroxy-6-methoxy-3-methyl-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-methano[1,4]diazonino[9,1,2-cd]indolizine-9-carboxamide(23-1 and 23-2)

Step 1. To a glass screw-top vial charged with Intermediate 22a (50 mg)was added THF (2.5 mL). The vial was cooled under argon to −80° C., thenlithium tri-sec-butylborohydride (1 M in THF, 90 μL, 1 equiv) was added.After 15 min at −80° C., the reaction was quenched with saturatedaqueous ammonium chloride, then extracted with ethyl acetate. Thecombined organic phases were washed once with sat aq sodium bicarbonate,then once with brine, then dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification by silica gel flash columnchromatography (25 to 100% ethyl acetate in hexane) yielded the desiredproduct. 1H NMR (400 MHz, Chloroform-d) δ 10.76 (t, J=5.6 Hz, 1H),7.64-7.49 (m, 3H), 7.39-7.28 (m, 4H), 6.67 (dd, J=8.7, 7.5 Hz, 2H), 5.46(d, J=10.2 Hz, 1H), 5.10 (d, J=10.2 Hz, 1H), 4.98 (td, J=6.9, 2.8 Hz,1H), 4.70-4.61 (m, 2H), 4.11-4.05 (m, 1H), 3.99 (d, J=14.9 Hz, 1H), 3.58(ddd, J=18.9, 11.2, 8.4 Hz, 1H), 3.39 (d, J=15.0 Hz, 1H), 3.02 (td,J=12.7, 2.6 Hz, 1H), 2.46 (ddd, J=13.0, 7.0, 2.7 Hz, 1H), 2.37-2.27 (m,1H), 2.22 (tdd, J=12.3, 6.5, 2.7 Hz, 1H), 2.03-1.94 (m, 1H), 1.83-1.72(m, 1H), 1.30 (d, J=7.1 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC30H26F3N3O5: 566.2, found: 566.2.

Step 2. To a glass screw-top vial charged with the product from Step 1(27 mg) was added methanol (1.4 mL), then sodium borohydride (1.8 mg,1.0 equiv). Vigorous gas evolution was observed during sodiumborohydride addition. After 10 min at 20° C., the reaction was quenchedwith saturated aqueous sodium bicarbonate, then extracted withdichloromethane. The combined organic phases were dried over magnesiumsulfate, filtered and concentrated in vacuo to give the desired product,which was carried forward to subsequent steps without furtherpurification. 1H NMR (400 MHz, Chloroform-d) δ 10.97 (t, J=5.6 Hz, 1H),7.67-7.57 (m, 2H), 7.42-7.30 (m, 3H), 6.67 (dd, J=8.7, 7.5 Hz, 2H), 5.38(d, J=10.0 Hz, 1H), 5.24 (d, J=10.1 Hz, 1H), 4.86 (dt, J=10.5, 6.7 Hz,1H), 4.68 (dd, J=14.5, 5.5 Hz, 1H), 4.58 (dd, J=14.5, 4.8 Hz, 1H),3.86-3.71 (m, 2H), 3.63 (dd, J=18.3, 9.3 Hz, 1H), 3.41 (d, J=14.7 Hz,1H), 3.20 (d, J=14.7 Hz, 1H), 2.35 (dd, J=12.6, 8.0 Hz, 1H), 2.06-1.92(m, 2H), 1.69 (ddd, J=14.5, 7.3, 3.8 Hz, 1H), 1.49-1.35 (m, 1H),1.33-1.22 (m, 1H), 1.18 (d, J=6.7 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcdfor C30H28F3N3O5: 568.2, found: 568.2.

Step 3. To a glass vial charged with the product from Step 2 (13 mg)under argon was added DMF (0.5 mL). The vial was cooled to 0° C. Sodiumhydride (60% in mineral oil, 1.2 mg, 1.3 equiv) was added. The reactionwas stirred at 0° C. for 5 min, then MeI (2.6 mg, 0.8 equiv) was added.The reaction was stirred at 0° C. for 45 min, then quenched withsaturated aq NH4Cl, and extracted into ethyl acetate. The organic phasewas washed with water, then brine. The combined aqueous phases wereextracted with more ethyl acetate. The combined organic phases weredried over MgSO₄, filtered, concentrated in vacuo. Silica gel flashcolumn chromatography (25 to 100% ethyl acetate in hexane) yielded thedesired product as a mixture with unreacted starting material. LCMS-ESI+(m/z): [M+H]+ calcd for C31H30F3N3O5: 582.2, found: 582.3.

Step 4. To the product mixture from Step 3 (7 mg) was added toluene(0.25 mL) then TFA (0.25 mL). The reaction was sealed under ambientatmosphere, and stirred in at 60° C. for 15 min. The reaction wasdiluted with acetonitrile and concentrated in vacuo. The crude wasredissolved in 1:1 DMF:water, and purified by reverse-phase preparativeHPLC (20 to 100% acetonitrile in water, 0.1% TFA) to yield 23-1 and23-2.

23-2: 1H NMR (400 MHz, Acetonitrile-d3) δ 10.79 (s, 1H), 6.84 (t, J=8.5Hz, 2H), 4.64-4.56 (m, 1H), 4.56 (s, 2H), 3.68 (d, J=3.4 Hz, 1H), 3.65(s, 1H), 3.63 (s, 1H), 3.52 (dd, J=10.4, 8.2 Hz, 1H), 3.42 (d, J=4.6 Hz,1H), 3.39 (d, J=2.7 Hz, 1H), 3.31 (s, 3H), 2.26 (dd, J=12.8, 7.9 Hz,1H), 2.21-1.99 (m, 2H), 1.51-1.36 (m, 1H), 1.19 (d, J=6.6 Hz, 3H),1.00-0.85 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C24H24F3N3O5:492.2, found: 492.2.

23-1: 1H NMR (400 MHz, Acetonitrile-d3) δ 10.84 (s, 1H), 6.84 (t, J=8.5Hz, 2H), 4.65-4.57 (m, 1H), 4.56 (d, J=5.6 Hz, 2H), 3.76 (dd, J=11.6,4.1 Hz, 1H), 3.66 (d, J=14.7 Hz, 1H), 3.63-3.47 (m, 2H), 3.44 (s, 1H),2.28 (dd, J=12.7, 7.8 Hz, 1H), 2.16-2.07 (m, 1H), 2.01 (dd, J=14.5, 7.3Hz, 1H), 1.71 (ddd, J=15.0, 7.6, 4.1 Hz, 1H), 1.55-1.42 (m, 1H),1.25-1.09 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C23H22F3N3O5:478.2, found: 478.2.

Example 24: HIV MT-4 Antiviral and Cytotoxicity Assay Antiviral Assay inMT-4 Cells

Compounds were tested in a high-throughput 384-well assay format fortheir ability to inhibit the replication of HIV-1 (IIIB) in MT-4 cells.Compounds were serially diluted (1:3) in DMSO on 384-well polypropyleneplates and further diluted 200-fold into complete RPMI media (10% FBS,1% P/S) using the Biotek Micro Flow and Labcyte ECHO acoustic dispenser.Each plate contained up to 8 test compounds, with negative (No DrugControl) and 5 μM AZT positive controls. MT-4 cells were pre-infectedwith 10 μL of either RPMI (mock-infected) or a fresh 1:250 dilution ofHIV-1 IIIB concentrated virus stock. Infected and uninfected MT-4 cellswere further diluted in complete RPMI media and added to each plateusing a Micro Flow dispenser. After 5 days incubation in a humidifiedand temperature controlled incubator (37° C.), Cell Titer Glo (Promega)was added to the assay plates and chemiluminescence read using anEnvision plate-reader. EC₅₀ values were defined as the compoundconcentration that causes a 50% decrease in luminescence signal, andwere calculated using a sigmoidal dose-response model to generate curvefits.

Cytotoxicity Assay in MT-4 Cells

Assays were performed as above except uninfected MT-4 cells were addedto each well containing test compound. In addition, 10 μM puromycin wasadded to the last column of each assay plate to assess a base level ofcytotoxicity.

Example 25: HIV MT-4 Serum Shift Antiviral Reporter Assay

To quantify the amount of protein binding to human serum, compounds wereserially diluted (1:3) in DMSO and acoustically transferred onto384-well assay plates via a Labcyte ECHO robot. Each plate contained upto 8 test compounds, including negative and positive controls, (DMSO, 5μM AZT respectively). Assay plates were prepared in duplicate, andtested in either CCM (cell culture media) or HS/CCM (human serum/cellculture media). MT-4 cells were first pre-infected with pLai RLucreporter virus for 2 h at 37° C., then further diluted in either CCM(RPMI media, 10% FBS, 1% P/S) or HS/CCM (RPMI media, 10% FBS, 50% HS, 1%P/S), and subsequently added to each plate using a Biotek Micro Flowdispenser. After a 72-h incubation in a humidified and temperaturecontrolled incubator (37° C.), Renilla Glo (Promega) was added to allassay plates and chemiluminescence read using an Envision plate-reader.EC₅₀ values were defined as the compound concentration that causes a 50%decrease in luminescence signal, and were calculated using a sigmoidaldose-response model to generate curve fits. To determine the amount ofprotein binding, EC₅₀ fold shifts (or EC₅₀ shifts) were calculated bydividing EC₅₀ (HS/CCM)/EC₅₀ (CCM).

Compounds of the present disclosure demonstrate antiviral activity inthis assay as depicted in Table 1 below. Accordingly, the compounds ofthe embodiments disclosed herein may be useful for treating theproliferation of the HIV virus, treating AIDS, or delaying the onset ofAIDS or ARC symptoms.

TABLE 1 Compound EC₅₀ CC₅₀ Antiviral Serum Shift RLuc No. (nM) (nM) CCM50% HS EC₅₀ shift 1 1.35 4299 0.299 8.707 29 2 2.26 6159 0.351 20.79 593 1.78 4935 0.175 3.107 18 4 3.09 5140 0.72 32.31 45 5 2.24 4041 0.2786.04 22 6 2.60 3681 7 3.80 3800 0.997 60.83 61 8-1 0.86 7382 0.429 25.4259 8-2 2.286 9-1 3.063 8084 0.685 200.38 292 9-2 1.234 5174 0.347 34.0698 9-3 1.06 6311 0.384 28.5 74 9-4 0.703 6395 0.388 5.186 13 10-1  4.989565 0.715 120.63 168.7 10-2  1.05 4123 0.417 21.07 50.5 10-3  3.31 94730.632 25.584 40.48 10-4  2.47 4608 0.405 3.297 8.14 11-1  3.996 500001.16 3.91 3.36 11-2  1.52 48.4 31.78 11-3  5.277 50000 4.08 7.565 1.8511-4  4.016 50000 1.02 20.51 20.13 12-1  1.54 9692 0.77 16.89 22 12-2 3.26 11082 1.136 98.434 86 12-3  4.47 14789 12-4  7.33 13-1  1.7 2782113-2  1.1 24660 13-3  9.5 10132 13-4  10.7 30737 14-1  1.1 2310 0.22 26121 14-2  0.73 2112 0.41 11 26 15 1.2 3729 0.29 51 174 16 2.8 7446 171.2 3169 0.13 1.1 8 18 10.7 25218 0.87 0.97 1 19-1  2.1 4597 19-2  0.861872 19-3  1.2 6953 20 0.83 3342 0.31 16 53 21-1  1.04 4838 0.26 27 10421-2  0.8 5371 0.27 12 45 22 1.8 1939 23-1  5.7 26584 23-2  2.5 141150.46 21 46

The data in Table 1 represents an average over time of each assay foreach compound. For certain compounds, multiple assays have beenconducted.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification areincorporated herein by reference, in their entirety to the extent notinconsistent with the present description.

From the foregoing it will be appreciated that, although specificembodiments have been described herein for purposes of illustration,various modifications may be made without deviating from the spirit andscope of the disclosure. Accordingly, the disclosure is not limitedexcept as by the appended claims.

1-195. (canceled)
 196. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 197. The compound ofclaim 196, or the pharmaceutically acceptable salt thereof, wherein thecompound is selected from the group consisting of:


198. The compound of claim 196, or the pharmaceutically acceptable saltthereof, wherein the compound is selected from the group consisting of:


199. The compound of claim 196, or the pharmaceutically acceptable saltthereof, wherein the compound is selected from the group consisting of:


200. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 196, or the pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient.
 201. Thepharmaceutical composition of claim 200, further comprising one, two,three, or four additional therapeutic agents.
 202. The pharmaceuticalcomposition of claim 201, wherein the additional therapeutic agent oragents are anti-HIV agents.
 203. The pharmaceutical composition of claim201, wherein the additional therapeutic agent or agents are HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors,gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsidpolymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokineticenhancers, other drugs for treating HIV, or combinations thereof. 204.The pharmaceutical composition of claim 201, wherein the additionaltherapeutic agent or agents comprise a HIV capsid inhibitor.
 205. Thepharmaceutical composition of claim 201, wherein the pharmaceuticalcomposition is for oral or parenteral administration.
 206. A kitcomprising a compound of claim 196, or a pharmaceutically acceptablesalt thereof, and instructions for use.
 207. The kit of claim 206,further comprising one, two, three, or four additional therapeutic agentor agents.
 208. The kit of claim 207, wherein the additional therapeuticagent or agents are anti-HIV agents.
 209. The kit of claim 207, whereinthe additional therapeutic agent or agents are HIV protease inhibitors,HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors,gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsidpolymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokineticenhancers, other drugs for treating HIV, or combinations thereof. 210.The kit of claim 207, wherein the additional therapeutic agent or agentscomprise a HIV capsid inhibitor.
 211. A method of treating an HIVinfection in a human having or at risk of having the infection,comprising administering to the human a therapeutically effective amountof a compound of claim 196, or a pharmaceutically acceptable saltthereof.
 212. The method of claim 211, further comprising administeringto the human a therapeutically effective amount of one, two, three, orfour additional therapeutic agents.
 213. The method of claim 212,wherein the additional therapeutic agent or agents are anti-HIV agents.214. The method of claim 212, wherein the additional therapeutic agentor agents are HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors,gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors,latency reversing agents, capsid polymerization inhibitors, HIV bNAbs,TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV,or combinations thereof.
 215. The method of claim 212, wherein theadditional therapeutic agent or agents comprise a HIV capsid inhibitor.